WO2019210203A1

WO2019210203A1 - Compositions and methods of targeting gpr35 for the treatment of inflammatory bowel conditions

Info

Publication number: WO2019210203A1
Application number: PCT/US2019/029398
Authority: WO
Inventors: Dermot P. Mcgovern; Janine Bilsborough; Stephan Targan; Manreet KAUR; Alka POTDAR; Robert Higuchi
Original assignee: Cedars-Sinai Medical Center; Precision Ibd, Inc.
Priority date: 2018-04-27
Filing date: 2019-04-26
Publication date: 2019-10-31
Also published as: TW202014217A

Abstract

Disclosed herein are methods, kits and compositions for treating a subject for an inflammatory bowel disease. These methods, kits and compositions may be particularly useful for subjects with single nucleotide polymorphisms in a G Protein-Coupled Receptor 35 (GPR35) encoding gene locus.

Description

COMPOSITIONS AND METHODS OF TARGETING GPR35 FOR THE TREATMENT OF

INFLAMMATORY BOWEL CONDITIONS

CROSS-REFERENCE

[0001] This application claims the benefit of US Provisional Application Serial Number 62/663,800 filed April 27, 2018, and US Provisional Application Serial Number 62/796,471 filed January 24, 2019, both of which are incorporated by reference herein in their entirety.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy created April 25, 2019, is named 52388-739_601_SL.txt and is 27,000 bytes in size.

BACKGROUND OF THE INVENTION

[0003] Millions of people are affected by inflammatory disease or conditions. A prominent inflammatory disease is inflammatory bowel disease (IBD). IBD has two common forms, Crohn’s disease (CD) and ulcerative colitis (UC), which are chronic, relapsing inflammatory disorders of the gastrointestinal tract. Each of these forms has various sub-conditions that are present in sub populations of CD and UC patients. Some CD and UC patients experience a rapid onset of sub- conditions, while others experience a relative delay.

[0004] Few treatment options are available to patients that suffer from IBD. Further, selecting a therapy that is appropriate for any individual patient at any given stage of their disease is complicated by the unpredictability of each individual’s prognosis. Current therapeutic regimens include one or more of anti-inflammatory medication (e.g., corticosteroids) and immunomodulatory therapy (e.g., anti-TNF therapy). However, nearly half of all patients treated with an anti-TNF therapy do not respond to the induction of the therapy, or experience a loss of response to the treatment after a period of time, during which, disease severity has progressed significantly. Therefore, there remains a significant need for targeted and effective treatment options that respond to the underlying immunopathogenesis of IBD.

SUMMARY OF THE INVENTION

[0005] G Protein-Coupled Receptor 35 (GPR35) is linked to inflammatory regulation, e.g. , by the presence of the receptor at the surface of immune specific cells, and by agonist activation leading to changes in immune response. In some aspects, the present disclosure provides associations between a GPR35 genotype, e.g., a genotype comprising a single nucleotide polymorphism (SNP) in GPR35, and an inflammatory disease, condition, or subclinical phenotype thereof. Practical applications of the associations between the provided genotypes and incidences of clinical and subclinical phenotypes in certain populations of individuals are described herein. For example, the genotypes of the present disclosure can be used to predict a risk that a subject will develop an inflammatory disease, condition, or a subclinical phenotype thereof. The genotypes are also useful to predict whether a patient diagnosed with some form of an inflammatory disease will develop a severe form of the disease, such as a subclinical phenotype. In some cases, the genotypes disclosed herein are associated with an variation in an expression of GPR35, which in some cases, means the genotypes can be used to identify a patient who may be suitable for treatment with a targeted GPR35 therapy (e.g., a patient carrying a genotype associated with a decreased in GPR35 may be suitable for a treatment with an activator of GPR35). In some cases, a subject is administered a therapeutic agent (e.g., GPR35 modulator) provided the genotype disclosed herein is detected in a sample obtained from the subject. Non-limiting examples of inflammatory diseases associated with the genotypes and/or treatments herein include inflammatory bowel diseases such as Crohn’s disease (CD) and ulcerative colitis (UC). Non-limiting examples of subclinical phenotypes include stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g. , ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, and spondylitis (Bechterew’s disease). Further practical applications disclosed herein include laboratory- based methods of detecting the instant genotypes, such as quantitative PCR (qPCR) and other hybridization based assays, as well as sequencing methodologies. Additional exemplary applications include selecting an appropriate therapy (e.g. , GPR35 modulator) based on the presence or absence of a genotype, and monitoring treatment.

[0006] In some aspects, methods herein comprise treating the inflammatory disease or condition with a modulator of GPR35 activity or expression, such as a compound of Formula I-XXVI. Further aspects comprise selecting a patient for treatment after a determination that the patient comprises a certain GPR35 genotype, e.g., the patient comprises a single nucleotide polymorphism (SNP) in a GPR35 gene locus.

[0007] In some aspects, disclosed herein is a method of treating a subject having an

inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124; and (b) if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. In some aspects, disclosed herein is a method of treating a subject having an inflammatory disease or condition, the method comprising: administering to the subject a modulator of GPR35 activity or expression, provided a biological sample from the subject has been determined to comprise a GPR35 genotype, wherein the GPR35 genotype comprises a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124. In some embodiments, the inflammatory disease or condition comprises inflammatory bowel disease (IBD). In some embodiments, the inflammatory disease or condition comprises a condition indicative of developing a subclinical phenotype of inflammatory bowel disease. In some embodiments, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. In some embodiments, the modulator of GPR35 activity or expression is an activator of GPR35. In some embodiments, the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

In some embodiments, determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. In some embodiments, the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to a sequence selected from SEQ ID NOS: 63-124.

[0008] In some aspects, disclosed herein is a primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises a sequence selected from SEQ ID NOS: 63-124; and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. In some embodiments, the nucleotide variance comprises: (I) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an“A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs4676401, (xiv) a“G” allele in rs2975786, (xv) an“A” allele in rs4676346, (xvi) an“A” allele in rs6437356, (xvii) a“C” allele in rs6745185, (xviii) a“G” allele in rs4676407, (xix) a“G” allele in rs2953156, (xx) a“C” allele in rs4335944, (xxi) an“A” allele in rs73999973, (xxii) an“A” allele in rs4676410, (xxiii) a“G” allele in rs4676405, (xxiv) a“G” allele in rs2953154, (xxv) an“A” allele in rs6732874, (xxvi) a“G” allele in rs55862430, (xxvii) an“A” allele in rsl2621598, (xxviii) an“A” allele in rs55919442, (xxix) an“A” allele in rs74991608, or (xxx) a“T” allele in rs34826997. In some embodiments, the nucleic acid amplification assay comprises polymerase chain reaction.

[0009] In some aspects, disclosed herein is a nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises: (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an “A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs4676401, (xiv) a“G” allele in rs2975786, (xv) an“A” allele in rs4676346, (xvi) an“A” allele in rs6437356, (xvii) a“C” allele in rs6745185, (xviii) a“G” allele in rs4676407, (xix) a“G” allele in rs2953156, (xx) a“C” allele in rs4335944, (xxi) an“A” allele in rs73999973, (xxii) an“A” allele in rs4676410, (xxiii) a“G” allele in rs4676405, (xxiv) a“G” allele in rs2953154, (xxv) an“A” allele in rs6732874, (xxvi) a“G” allele in rs55862430, (xxvii) an“A” allele in rsl2621598, (xxviii) an“A” allele in rs55919442, (xxix) an“A” allele in rs74991608, or (xxx) a“T” allele in rs34826997; and wherein the probe comprises a detectable label.

[0010] In some aspects, disclosed herein is a nucleic acid probe comprising a sequence selected from SEQ ID NOS: 63-124, and a detectable label. In some aspects, disclosed herein is a nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of a sequence selected from SEQ ID NOS: 32-124, and a detectable label.

[0011] In some aspects, disclosed herein is a method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulator of GPR35; wherein the GPR35 genotype composes a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124. In some embodiments, determining comprises performing or having performed a genotyping assay on the biological sample from the subject. In some embodiments, the genotypmg assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to a sequence selected from SEQ ID NOS: 63-124. In some embodiments, the inflammatory disease or condition comprises inflammatory bowel disease (IBD). In some embodiments, the inflammatory disease or condition comprises a condition indicative of developing a subclinical phenotype of inflammatory bowel disease. In some embodiments, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. In some embodiments, the modulator of GPR35 activity or expression is an activator of GPR35. In some embodiments, the modulator of GPR35 activity or expression comprises a compound selected from Formulas I -XXVI. [0012] In some aspects, disclosed herein is use of a compound selected from Formulas I-XXVI to treat a subject determined to comprise a condition indicative of developing an inflammatory bowel disease subcbnical phenotype, wherein the subclinical phenotype comprises stricturing, non- stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g. , ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof.

[0013] In some aspects, disclosed herein is use of a compound selected from Formulas I-XXVI to treat a subject comprising a GPR35 genotype comprising a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124.

[0014] In some aspects, disclosed herein is a method of treating a subject having an

inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl l33726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, rs78571781, or a genotype comprising a single nucleotide polymorphism in linkage disequilibrium therewith, (ii) a sequence selected from SEQ ID NOS: 1-31, (iii) a sequence selected from SEQ ID NOS: 32-62, (iv) a sequence selected from SEQ ID NOS: 63-101, (v) a sequence selected from SEQ ID NOS: 102-124, or (v) or a combination of (i)-(iv); and (b) if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. In some embodiments, the inflammatory disease or condition comprises inflammatory bowel disease, Crohn’s disease, ulcerative colitis, or a subclinical phenotype of inflammatory bowel disease, Crohn’s disease, or ulcerative colitis. In some embodiments, the modulator of GPR35 activity or expression is an activator of GPR35. In some embodiments, the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. In some embodiments, determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. In some embodiments, the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, (ii) a sequence selected from SEQ ID NOS: 1-31, (rii) a sequence selected from SEQ ID NOS: 32-62, (iv) a sequence selected from SEQ ID NOS: 63-101, (v) a sequence selected from SEQ ID NOS: 102-124, or (v) or a combination of (i)-(iv).

[0015] In some aspects, disclosed herein is a primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) a sequence selected from SEQ ID NOS: 32-62, (ii) a sequence selected from SEQ ID NOS: 63-101, (iii) a sequence selected from SEQ ID NOS: 102-124, or (iv) or a combination of (i)-(iii); and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. In some embodiments, the nucleotide variance comprises: (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an“A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs4676401, (xiv) a“G” allele in rs2975786, (xv) an“A” allele in rs4676346, (xvi) an“A” allele in rs6437356, (xvii) a“C” allele in rs6745185, (xviii) a“G” allele in rs4676407, (xix) a“G” allele in rs2953156, (xx) a“C” allele in rs4335944, (xxi) an“A” allele in rs73999973, (xxii) an“A” allele in rs4676410, (xxiii) a“G” allele in rs4676405, (xxiv) a“G” allele in rs2953 l54, (xxv) an“A” allele in rs6732874, (xxvi) a“G” allele in rs55862430, (xxvii) an“A” allele in rsl262l598, (xxviii) an“A” allele in rs559l9442, (xxix) an“A” allele in rs74991608, or (xxx) a“T” allele in rs34826997. In some embodiments, the nucleic acid amplification assay comprises polymerase chain reaction.

[0016] In some aspects, disclosed herein is a nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises: (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs374917l, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an “A” allele in rs2975782, (vi) a“C” allele in rs3749l72, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs4676401, (xiv) a“G” allele in rs2975786, (xv) an“A” allele in rs4676346, (xvi) an“A” allele in rs6437356, (xvii) a“C” allele in rs6745185, (xviii) a“G” allele in rs4676407, (xix) a“G” allele in rs2953 l56, (xx) a“C” allele in rs4335944, (xxi) an“A” allele in rs73999973, (xxii) an“A” allele in rs46764l0, (xxiii) a“G” allele in rs4676405, (xxiv) a“G” allele in rs2953l54, (xxv) an“A” allele in rs6732874, (xxvi) a“G” allele in rs55862430, (xxvii) an“A” allele in rsl2621598, (xxviii) an“A” allele in rs55919442, (xxix) an“A” allele in rs74991608, or (xxx) a“T” allele in rs34826997; and wherein the probe comprises a detectable label.

[0017] In some aspects, disclosed herein is a nucleic acid probe comprising a sequence selected from SEQ ID NOS: 32-124, and a detectable label.

[0018] In some aspects, disclosed herein is a nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of a sequence selected from SEQ ID NOS: 32-124, and a detectable label.

[0019] In some aspects, disclosed herein is a method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulator of GPR35 activity or expression; wherein the GPR35 genotype comprises: (i) rs! 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs467640l, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs7908670l, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl093362l, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, rs78571781, or a genotype comprising a single nucleotide polymorphism in linkage disequilibrium therewith, (ii) a sequence selected from SEQ ID NOS: 1-31, (iii) a sequence selected from SEQ ID NOS: 32-62, (iv) a sequence selected from SEQ ID NOS: 63-101, (v) a sequence selected from SEQ ID NOS: 102-124, or (v) or a combination of (i)-(iv). In some embodiments, the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. In some

embodiments, the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rsl l3435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl 0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl l6803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474l50, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, (ii) a sequence selected from SEQ ID NOS: 1-31, (iii) a sequence selected from SEQ ID NOS: 32-62, (iv) a sequence selected from SEQ ID NOS: 63-101, (v) a sequence selected from SEQ ID NOS: 102-124, or (v) or a combination of (i)-(iv). In some embodiments, the inflammatory disease or condition comprises inflammatory bowel disease, Crohn’s disease, ulcerative colitis, or a subclinical phenotype of inflammatory bowel disease, Crohn’s disease, or ulcerative colitis. In some embodiments, the modulator of GPR35 activity or expression is an activator of GPR35. In some embodiments, the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[0020] In some aspects, disclosed herein is the use of a compound selected from Formulas I- XXVI to treat a subclinical phenotype of an inflammatory bowel disease comprising stricturing, non- stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g. , ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof.

[0021] In some aspects, disclosed herein is the use of a compound selected from Formulas I- XXVI to treat a subject comprising a GPR35 genotype comprising: (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, rs78571781, or a genotype comprising a single nucleotide polymorphism in linkage disequilibrium therewith, (ii) a sequence selected from SEQ ID NOS: 1-31, (iii) a sequence selected from SEQ ID NOS: 32-62, (iv) a sequence selected from SEQ ID NOS: 63-101, (v) a sequence selected from SEQ ID NOS: 102-124, or (v) or a combination of (i)-(iv).

DETAILED DESCRIPTION OF THE DISCLOSURE

[0022] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Certain Terminologies

[0023] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the embodiments provided may be practiced without these details. Unless the context requires otherwise, throughout the specification and claims which follow, the word“comprise” and variations thereof, such as,“comprises” and“comprising” are to be construed in an open, inclusive sense, that is, as“including, but not limited to.” As used in this specification and the appended claims, the singular forms“a,”“an,” and“the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term“or” is generally employed in its sense including“and/or” unless the content clearly dictates otherwise. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.

[0024] As used herein, Ci-C_* includes Ci-C₂, C₁-C₃ . . . Ci-C_x. Ci-C_* refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).

[0025] An“alkyl” group refers to an aliphatic hydrocarbon group. The alkyl groups may or may not include units of unsaturation. The alkyl moiety may be a“saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon -carbon double bond or a carbon -carbon triple bond). The alkyl group may also be an“unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

[0026] The“alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as“1 to 6” refers to each integer in the given range; e.g. ,“1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as C_|-C„alkyl or similar designations. By way of example only,“Ci-C₆alkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n- pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

[0027] An“alkoxy” refers to a“-O-alkyl” group, where alkyl is as defined herein.

[0028] The term“alkenyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atoms -C(R)=CR₂, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. Non-limiting examples of an alkenyl group include -CH=CH₂, -C(CH₃)=CH₂, - CH=CHCH₃, -CH=C(CH₃)₂ and -C(CH₃)=CHCH₃. The alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a“cycloalkenyl” group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).

[0029] The term“alkynyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms -CºC-R, wherein R refers to the remaining portions of the alkynyl group. Non-limiting examples of an alkynyl group include -CºCH, -CºCCH₃, -CºCCH₂CH₃ and -CºCCH₂CH₂CH₃. The“R” portion of the alkynyl moiety may be branched, straight chain, or cyclic. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).

[0030] ‘Ammo” refers to a -NH₂ group.

[0031] The term“alkylamine” or“alkylamino” refers to the -N(alkyl) H_v group, where alkyl is as defined herein and x and y are selected from the group x=l, y=l and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system.“Dialkylamino” refers to a -N(alkyl)₂ group, where alkyl is as defined herein.

[0032] The term“aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0033] As used herein, the term“aryl” refers to an aromatic nng wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0034] “Carboxy” refers to -C0₂H. In some embodiments, carboxy moieties may be replaced with a“carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisostere s of a carboxylic acid include, but are not limited to,

an e e.

[0035] The term“cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.

[0036] The terms“heteroaryl” or, alternatively,“heteroaromatic” refers to an aryl group that includes one or more nng heteroatoms selected from nitrogen, oxygen and sulfur. An /V-containmg “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

[0037] A“heterocycloalkyl” group or“heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).

[0038] The term“halo” or, alternatively,“halogen” means fluoro, chloro, bromo and iodo.

[0039] The term“haloalkyl” refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non -limiting examples of haloalkyls include -CH₂C1, -CF₃, -CHF₂, -CH₂CF₃, -CF₂CF₃, and the like.

[0040] The terms“fluoroalkyl” and“fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non -limiting examples of fluoroalkyls include - CF₃, -CHF₂, -CH₂F, -CF1₂CF₃, -CF₂CF₃, -CF₂CF₂CF₃, -CF(CH₃)₃, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF₃, -OCHF₂, -OCH₂F, -OCH₂CF₃, -OCF₂CF₃, -OCF₂CF₂CF₃, - OCF(CH₃)₂, and the like.

[0041] The term“heteroalkyl” refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH₂-0-CH₃, -CH₂-CH₂-0-CH₃, -CH₂-NH-CH₃, - CH₂-CH₂-NH-CH₃, -CH₂-N(CH₃)-CH₃, -CH₂-CH₂-NH-CH₃, -CH₂-CH₂-N(CH₃)-CH₃, -CH₂-S-CH₂- CH₃, -CH₂-CH₂-S(0)-CH₃, -CH₂-CH₂-S(0)₂-CH₃, -CH₂-NH-OCH₃, -CH₂-0-Si(CH₃)₃, -CH₂-CH=N- OCH₃, and -CH=CH-N(CH₃)-CH₃. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH₂-NH-OCH₃ and -CH₂-0-Si(CH₃)₃. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms.

[0042] The term“bond” or“single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

[0043] The term“moiety” refers to a specific segment or functional group of a molecule.

Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0044] As used herein, the substituent“R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0045] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.

[0046] The term“optionally substituted” or“substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C _rC₍,alkylalkyne. halo, acyl, acyloxy, -C0₂H, -C0₂-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. -NH₂, -NHR, -N(R)₂), and the protected derivatives thereof. By way of example, an optional substituents may be L^SR^S, wherein each L^s is independently selected from a bond, -0-, -C(=0)-, -S-, -S(=0)-, -S(=0)₂-, -NH-, -NHC(O)-, -C(0)NH-, S(=0)₂NH-, -NHS(=0)₂, - OC(0) H-, -NHC(0)0-, -(Ci-C₆alkyl)-, or -(C₂-C₆alkenyl)-; and each R^s is independently selected from among H, (Ci-C₆alkyl), (C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C

C₆heteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.

[0047] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.

[0048] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, / -tolucncsulfonic acid, salicylic acid, and the like. Exemplaiy salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates,

benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates,

methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0049] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine,

2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N /V-d i ben zy 1 eth y 1 c n e di am i n c . chloroprocaine, hydrabamine, choline, betaine,

ethylenediamine, ethylenedianiline, A'-methyl gl ucam i ne . glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A'-cth lpipcridinc. polyamine resins, and the like. See Berge et al., supra.

[0050] The term“about” or“approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e g , the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” should be assumed to mean an acceptable error range for the particular value.

[0051] As used herein“consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure, such as compositions for treating skin disorders like acne, eczema, psoriasis, and rosacea.

[0052] As used herein, the terms“homologous,”“homology,” or“percent homology” when used herein to describe to an amino acid sequence or a nucleic acid sequence, relative to a reference sequence, can be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad.

Sci. USA 87: 2264-2268, 1990, modified as in Proc. Natl. Acad. Sci. USA 90:5873-5877, 1993). Such a formula is incorporated into the basic local alignment search tool (BUAST) programs of Altschul et al. (J. Mol. Biol. 215: 403-410, 1990). Percent homology of sequences can be determined using the most recent version of BLAST, as of the filing date of this application.

[0053] The terms“increased,” or“increase” are used herein to generally mean an increase by a statically significant amount. In some embodiments, the terms“increased,” or“increase,” mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, standard, or control. Other examples of“increase” include an increase of at least 2-fold, at least 5-fold, at least 10- fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or more as compared to a reference level.

[0054] The terms,“decreased” or“decrease” are used herein generally to mean a decrease by a statistically significant amount. In some embodiments, “decreased” or“decrease” means a reduction by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., absent level or non-detectable level as compared to a reference level), or any decrease between 10-100% as compared to a reference level. In the context of a marker or symptom, by these terms is meant a statistically significant decrease in such level. The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and is preferably down to a level accepted as within the range of normal for an individual without a given disease.

[0055] In some embodiments, the terms“patient” or“subject” are used interchangeably herein, and encompass mammals. Non -limiting examples of mammal include, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. The term“animal” as used herein comprises human beings and non-human animals. In one embodiment, a“non-human animal” is a mammal, for example a rodent such as rat or a mouse.

[0056] Non-limiting examples of“biological sample” include any biological material from which nucleic acids and/or proteins can be obtained. As non-limiting examples, this includes whole blood, peripheral blood, plasma, serum, saliva, mucus, urine, semen, lymph, fecal extract, cheek swab, cells or other bodily fluid or tissue, including but not limited to tissue obtained through surgical biopsy or surgical resection. In various embodiments, the sample comprises tissue from the large and/or small intestine. In various embodiments, the large intestine sample comprises the cecum, colon (the ascending colon, the transverse colon, the descending colon, and the sigmoid colon), rectum and/or the anal canal. In some embodiments, the small intestine sample comprises the duodenum, jejunum, and/or the ileum. Alternatively, a sample can be obtained through primary patient derived cell lines, or archived patient samples in the form of preserved samples, or fresh frozen samples.

[0057] In some embodiments,“treatment” and“treating” as used herein refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition, prevent the pathologic condition, pursue or obtain good overall survival, or lower the chances of the individual developing the condition even if the treatment is ultimately unsuccessful. In some aspects provided herein, subjects in need of treatment include those already with a disease or condition, as well as those susceptible to develop the disease or condition or those in whom the disease or condition is to be prevented.

[0058] In some embodiments, the term“gene,” as used herein, refers to a segment of nucleic acid that encodes an individual protein or RNA (also referred to as a“coding sequence” or“coding region”), optionally together with associated regulatory region such as promoter, operator, terminator and the like, which may be located upstream or downstream of the coding sequence.

[0059] In some embodiments, the term,“genotype” as disclosed herein, refers to the chemical composition of polynucleotide sequences within the genome of an individual. In some embodiments, the genotype comprises single nucleotide variant (SNV), a single nucleotide polymorphism (SNP), or and indel (insertion or deletion, of a nucleobase within a polynucleotide sequence). In some embodiments, a genotype for a particular SNV, SNP, or indel is heterozygous. In some embodiments, a genotype for a particular SNV, SNP, or indel is homozygous.

[0060] In some embodiments, the term,“single nucleotide variant” or“single nucleotide variation” or SNV, as disclosed herein, refers to a variation in a single nucleotide within a polynucleotide sequence. The variation of an SNV may have multiple different forms. A single form of an SNV is referred to as an“allele.” An SNV can be mono-, bi-, tri, or tetra-allelic. An SNV may include a“risk allele,” a“protective allele,” or neither. By way of example, a reference polynucleotide sequence reading 5’ to 3’ is TTACG. A SNV at allele position 3 (of 5’-TTACG-3’) comprise a substitution of the reference allele,“A” to a non-reference allele,“C.” If the“C” allele of the SNV is associated with an increased probability of developing a phenotypic trait, the allele is considered a “risk” allele. However, the same SNV may also comprise a substitution of the“A” allele to a“T” allele at position 3. If the T allele of the SNV is associated with a decreased probability of developing a phenotypic trait, the allele is considered a“protective” allele. The SNV may comprise a single nucleotide polymorphism (SNP), in some cases, which is an SNV observed in at least 1% of a given population. In some embodiments, the SNV is represented by an“rs” number, which refers to the accession of reference cluster of one more submitted SNVs in the dbSNP bioinformatics database as of the filing date of this patent application, and which is included within a sequence that comprises the total number of nucleobases from 5’ to 3’. In some embodiments, a SNV may be further defined by the position of the SNV (nucleobase) within the dbSNP sequence, the position of which is always with reference to 5’ length of the sequence plus 1. In some embodiments, a SNV is defined as the genomic position in a reference genome and the allele change (e.g. chromosome 7 at position 234,123,567 from G allele to A allele in the reference human genome build 37). In some

embodiments, the SNV is defined as the genomic position identified with [brackets] in a sequence of Table 30 (e.g., SEQ ID NOS: 1-31).

[0061] In some embodiments, the term,“indel,” as disclosed herein, refers to an insertion, or a deletion, of a nucleobase within a polynucleotide sequence. An indel can be mono-, bi-, tri, or tetra- allelic. An indel may be“risk,” a“protective,” or neither, for a phenotypic trait. In some embodiments, the indel is represented by an“rs” number, which refers to the accession of reference cluster of one more submitted indels in the dbSNP biomformatics database as of the filing date of this patent application, and which is included in a sequence that comprises the total number of nucleobases from 5’ to 3’ . In some embodiments, an indel may be further defined by the position of the insertion/deletion within the dbSNP sequence, the position of which is always with reference to the 5’ length of the sequence plus 1. In some embodiments, an indel is defined as the genomic position in a reference genome and the allele change. In some embodiments, the indel is defined as the genomic position identified with [brackets] in a sequence of Table 30 (e.g. , SEQ ID NOS: 1-31).

[0062] In some embodiments,“haplotype” as used herein, encompasses a group of one or more genotypes, SNVs, SNPs, or indels, which tend to be inherited together in a reference population. In some embodiments, a haplotype comprises particular SNVs, SNPs, or indels, and any SNV, SNP, or indel in linkage disequilibrium therewith.

[0063] In some embodiments,“linkage disequilibrium,” or“LD,” as used herein refers to the non-random association of alleles or indels in different gene loci in a given population. LD may be defined by a D’ value corresponding to the difference between an observed and expected allele or indel frequencies in the population (D=Pab-PaPb), which is scaled by the theoretical maximum value of D. LD may be defined by an r² value corresponding to the difference between an observed and expected unit of risk frequencies in the population (D=Pab-PaPb), which is scaled by the individual frequencies of the different loci. In some embodiments, D’ comprises at least 0.20. In some embodiments, r² comprises at least 0.70.

[0064] In some embodiments, the term,“serological marker,” as used herein refers to a biological marker found in semm that are associated with, or involved in disease pathology. Non limiting examples of biological markers include proteins, nucleic acids, or other compounds with a physiological function in a subject. In some embodiments, serological markers comprising antibodies against microbial antigens or autoantibodies. Non-limiting examples of serological markers comprising antibodies include anti-Saccharomyces cerevisiae (ASCA) anti-laminaribioside (ALCA), anti-chitobioside (ACCA), anti-mannobioside (AMCA), anti-laminarin (anti-L) and anti-chitin (anti- C), anti-outer membrane porin C (anti-OmpC), anti-Cbirl flagellin and anti-12 antibody, and anti neutrophil cytoplasmic autoantibodies (pANCA).

[0065] In some embodiments, the term,“non-responsive” to a therapy, as disclosed herein, refers to a subject not responding to the induction of a therapy (primary non-response), or loss of response during maintenance after a successful induction of the therapy (secondary loss of response). In some embodiments, the induction of a therapy comprises 1, 2, 3, 4, or 5, doses of the therapy. In some embodiments, loss of response is characterized by a reappearance of symptoms consistent with a flare after an initial response to the therapy. Non-limiting examples of therapies include anti -tumor necrosis factor (TNF) alpha therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekmumab), Thalidomide, and Cytoxin. A therapy that is administered to a subject who has been determined to be “non-responsive” to any of the above therapies may be referred to herein as a“secondary” or“second- line” therapeutic.

[0066] In some embodiments, the term“anti-tumor necrosis factor (TNF) non-response,” as used herein, refers to a subject not responding to the induction of an anti-TNF therapy (primary non response), or loss of response during maintenance after a successful induction of the anti-TNF therapy (secondary loss of response). In some embodiments, the induction of the anti-TNF therapy comprises 1, 2, 3, 4, or 5, doses of the therapy. In some embodiments, loss of response is characterized by a reappearance of symptoms consistent with a flare after an initial response to the anti-TNF therapy.

[0067] In some embodiments, the term“medically refractory,” or“refractory,” as used herein, refers to the failure of a standard treatment to induce remission of a disease. In some embodiments, the disease comprises an inflammatory disease disclosed herein. A non-limiting example of refractory inflammatory disease includes refractory Crohn’s disease, and refractor ulcerative colitis (e.g., mrUC). Non-limiting examples of standard treatment of inflammatory disease include

glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, and Cytoxin. [0068] Provided throughout this application are kits, compositions and methods for the treatment of IBD. It is should be understood that kits and compositions disclosed herein may be used according to, or for, methods described herein. Conversely, methods disclosed herein may appropriately employ compositions disclosed herein.

METHODS

[0069] Inflammatory Disease or Condition

[0070] Disclosed herein, in some aspects, are methods of treating, or determining whether or not a therapeutic agent targeting GPR35 is suitable to treat, an inflammatory disease or condition in a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the inflammatory condition or disease comprises a condition that involves chronic inflammation of the body caused by pathogens, viruses, foreign bodies or overactive immune responses. In some embodiments, the inflammatory disease comprises inflammatory bowel disease (IBD). The primary forms of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). However, additional IBDs include microscopic colitis, diversion colitis, Behcet's disease and indeterminate colitis. CD may affect almost any portion of the GI tract. UC generally affects the anus and rectum. Non-limiting symptoms of IBDs include diarrhea, abdominal pain, weight loss, and anemia. Notably, there is a broad spectrum of prognoses for any given IBD making it difficult to decide on a standard or optimal course of treatment for any given patient.

[0071] Other non-limiting examples of inflammatory disease or conditions include, but are not limited to, rheumatoid arthritis, multiple sclerosis, psoriasis, chronic colitis, pancreatitis, leukopenia, and chronic asthma. In some embodiments, the subject presents fibrotic or fibrostenotic disease. Non limiting examples of fibrotic or fibrostenotic diseases include colonic fibrosis, pulmonary fibrosis, primary sclerosing cholangitis, progressive systemic sclerosis, or fibrostenosis of a small and/or large intestine. In some embodiments, the subject is susceptible to, or is inflicted with, thiopurine toxicity, or a disease caused by thiopurine toxicity (such as pancreatitis or leukopenia). In further embodiments provided, the subject is non-responsive to a therapy comprising anti-TNF alpha therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, or Cytoxin.

[0072] Subject

[0073] Disclosed herein, in some embodiments, are methods of treating, diagnosing, prognosing, or monitoring, an inflammatory disease or condition in a subject. In some instances, the subject is a mammal. In some embodiments, the subject comprises a mouse, rat, guinea pig, rabbit, chimpanzee, or farm animal. In some instances, the subject is human. In some instances, the subject is diagnosed with the disease or condition disclosed herein. Non-limiting methods for diagnosis using existing indices and scoring systems include Crohn's Disease Activity Index (CDAI), Ulcerative Colitis Disease Activity Index (UCDAI), guidelines from American College of Gastroenterology (ACG) and European Crohn's and Colitis Organization (ECCO), patient-reported outcomes (PRO-2), Harvey - Bradshaw Index, Van Hess Index, Perianal Disease Activity Index (PDAI), Rachmilewitz score, Mayo score, Powell-Tuck index, Patient Simple Clinical Colitis Activity Index (P-SCCAI), Lichtiger index, Seo index, Inflammatory Bowel Disease Questionnaire (IBDQ), Manitoba IBD Index, Crohn's Disease Endoscopic Index of Severity (CDEIS), Simple Endoscopic Score for Crohn Disease (SES- CD), Lewis score (capsule endoscopy), Rutgeert’s Score, and the Montreal Classification, and IBD questionnaire. In some instances, the subject is not diagnosed with the disease or condition. In some instances, the subject is suffering from a symptom related to a disease or condition disclosed herein (e.g., abdominal pain, cramping, diarrhea, rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration, and malnutrition, anemia, or ulcers).

[0074] In some embodiments, the subject is susceptible to, or is inflicted with, thiopurine toxicity, or a disease caused by thiopurine toxicity (such as pancreatitis or leukopenia). In further embodiments provided, the subject is, or is suspected of being, non-re sponsive to a standard treatment (e.g., anti- TNF alpha therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, or Cytoxin). In some cases, the subject is not responsive to the induction of said therapy. In some cases, the subject loses response to said standard treatment after a period of time during treatment.

[0075] G Protein-Coupled Receptor 35 (GPR35)

[0076] G Protein -Coupled Receptor 35 (GPR35) is a receptor for kynurenic acid, an intermediate in the tryptophan metabolic pathway. GPR35 mediates calcium mobilization and inositol phosphate production. GPR35, and nucleic acids encoding GPR35, are characterized by NCBI Entrez Gene ID 2859. Studies show that GPR35 is linked to inflammatory regulation, either by the presence of the receptor at the surface of immune specific cells, or by agonists activation leading to changes in immune response. Accordingly, it is hypothesized that GPR35, and nucleic acids encoding GPR35, play a role is inflammatory disease pathology making GPR35 an attractive therapeutic target to treat inflammatory diseases or conditions. In some instances, methods disclosed herein comprise assaying a biological sample for the presence of a single nucleotide polymorphism (SNP) in a GPR35 gene locus. In some instances, methods disclosed herein comprise detecting a presence of a SNP in a GPR35 gene locus. In some instances, methods disclosed herein comprise detecting an absence of a SNP in a GPR35 gene locus. In in some instances, the methods disclosed herein are used to treat a subject with an inflammatory disease or condition.

[0077] GPR35 Single Nucleotide Polymorphism (GPR35 SNPS)

[0078] Disclosed herein, in some aspects, are methods that comprise obtaining a biological sample from a subject; assaying for the presence of a single nucleotide polymorphism (SNP) in a GPR35 gene locus selected from Table 1, or a SNP in linkage disequilibrium therewith. In some instances, methods further comprise administering a therapeutic agent that modifies at least one of GPR35 expression and GPR35 activity, provided the presence of the SNP is determined. Methods of detection disclosed herein are useful for determining the presence of a SNP. The SNP may be in a coding region of GPR35 (e.g., an exon). The SNP may be in a non-coding region of GPR35 (e.g., an intron). The SNP may be in non-coding gene regulatory regions, thereby affecting GPR35 expression/activity. A SNP in linkage disequilibrium with a GPR35 SNP is inherited with the GPR3 SNP. The SNP in linkage disequilibrium may not be located in the GPR35 gene locus. In some embodiments, the SNP is defined as the genomic position identified with [brackets] in the polynucleotide sequence of any one of SEQ ID NOS: 1-31 shown in Table 30.

[0079] Disclosed herein, in some embodiments, are GPR35 SNPs that are associated with a risk of having, or developing, a disease or condition. A presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, the disease or condition. In some instances, a GPR35 SNP disclosed herein is associated with inflammatory bowel disease (IBD). In some instances, a GPR35 SNP disclosed herein is associated with Crohn’s disease (CD). In some instances, a GPR35 SNP disclosed herein is associated with ulcerative colitis (UC). In some instances, a GPR35 SNP disclosed herein is associated with stricturing. Stricturing may be described as the presence of a stricture or narrowed region of the intestine. The stricture may comprise scar tissue. In some instances, a GPR35 SNP disclosed herein is associated with penetrating.

Penetrating may be described as the presence of a fistula. Fistulae may occur between sections of the bowel or between the bowel and skin. In some instances, the stricturing, penetrating, and/or stricturing and penetrating disease is localized in the ileum, colon, or ileocolonic region of the intestine. In some instances, the GPR35 SNP is associated with stricturing, penetrating, and/or stricturing and penetrating disease is localized in the ileum, colon, or ileocolonic region of the intestine. In some instances, a GPR35 SNP disclosed herein is associated with perianal Crohn’s disease. Perianal CD typically involves inflammation around the anus. Perianal CD may be a sub-condition of CD or its own condition. In some instances, a GPR35 SNP disclosed herein is associated with pancolitis. Pancolitis may be described as UC that is localized throughout the entire large intestine (right colon, left colon, transverse colon, descending colon and rectum). In some instances, the GPR35 SNP is associated with arthralgia. Non-limiting examples of arthralgia include osteoarthritis, rheumatoid arthritis, spondylitis, gout, post-traumatic arthritis, migratory arthritis, bursitis, and neuropathic arthropathy. In some instances, the GPR35 SNP is associated with medically refractory disease, characterized by the failure of a standard treatment to induce remission of a disease in a subject. In some embodiments, the disease comprises an inflammatory disease disclosed herein. A non-limiting example of refractory inflammatory disease includes refractory Crohn’s disease (mrCD), and refractor ulcerative colitis (mrUC).

[0080] Disclosed herein, in some embodiments, are GPR35 SNPs that are associated with subclinical phenotype. In some instances the subclinical phenotype is associated with one or the disease or conditions disclosed herein. In some embodiments, a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, the subclinical phenotype. A subclinical phenotype may be a specific diagnosable disease or condition, or metric to measure disease progression that is characteristic of severe or unusual forms of disease Non-limiting examples of IBD subclinical phenotypes include, but are not limited to, non-stricturing disease, stricturing disease, stricturing and penetrating disease, and perianal Crohn’s disease (pCD). Time to a first surgery, and time to second surgery, are subclinical phenotypes used to identify subjects at risk for severe forms of disease. In the context of inflammatory bowel disease, a time to first surgery may be a time from a symptom of the inflammatory bowel disease to a surgery. The time to first surgery may be a time from first diagnosis of the IBD to a time of a first surgery. The time to second surgery may be a time from a first surgery to the time of a second surgery. The first and/or second surgery may comprise surgery on at least a portion of the gastrointestinal tract of the subject. Non-limiting surgeries include an intestinal resection, colectomy, perianal surgery, and stricturoplasty. The symptom may be a symptom described herein. The portion of the gastrointestinal tract may be selected from the anus, the colon, the large intestine, the small intestine, the stomach, and the esophagus.

[0081] Disclosed herein, in some embodiments, are GPR35 SNPs that are associated with a faster progression to surgery, as compared to an individual who does not carry the GPR35 SNP. A faster progression to surgery is indicative of complicated disease, often resistant to therapy. In some embodiments, a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, complicated disease behavior characterized by a faster progression to a first and/or second surgery. A“first surgery,” as disclosed herein, refers to the first surgical treatment of a disease or disorder described herein in a subject. A“second surgery,” as used here, refers to the second surgical treatment of the same disease or disorder in the subject. In some instances, a GPR35 SNP disclosed herein is associated with a first time from a first symptom of the inflammatory bowel disease to a first surgery. In some instances, a GPR35 SNP disclosed herein is associated with a first time from a diagnosis of the inflammatory bowel disease to a first surgery. In some instances, a GPR35 SNP disclosed herein is associated with a time from an age to a first surgery. The first time may be about one year to about fifteen years. The first time may be about two years to about twelve years. The first time may be about four years to about ten years. The first time may be about four years to about eight years.

[0082] In some instances, a GPR35 SNP disclosed herein is associated with a second time from a first surgery to a second surgery. The second time may be about one year to about fifteen years. The second time may be about two years to about twelve years. The second time may be about four years to about ten years. The second time may be about four years to about eight years. The time to first surgery for patients carrying a risk allele may be about three years to about nine years. The time to first surgery for patients carrying a risk allele may be about four years to about eight years. The time to first surgery for patients for a risk allele may be about three years to about seven years. The time to first surgery for patients for a risk allele may be about seven years. The time to first surgery for patients homozygous for a non-risk minor allele may be about ten years. The time to first surgery for patients homozygous for a non-risk minor allele may be greater than about ten years. The time to first surgery for patients homozygous for a non-risk minor allele may be at least about ten years.

[0083] Disclosed herein, in some embodiments, are GPR25 SNPs associated with non-response or loss of response to a standard therapy. In some embodiments, a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, non response or loss of response to a standard therapy. Non-limiting examples of standard therapy of inflammatory disease include glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy

(vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, and Cytoxin. In some instances, a GPR35 SNP disclosed herein is associated with a combination of IBD, CD, UC, mrUC, mrCD, stricturing, penetrating, perianal CD, arthalgia, non-response to a standard therapy, and pancolitis.

[0084] Disclosed herein, in some embodiments are GPR35 SNP is associated with the expression of serological markers. In some embodiments, a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, a disease or condition or subtype of the disease or condition, associated with a presence of a microbiome. Non-limiting examples of serological markers include mti-Saccharomyces cerevisiae (ASCA) anti-laminaribioside (ALCA), anti-chitobioside (ACCA), anti-mannobioside (AMCA), anti-laminarin (anti-L) and anti- chitin (anti-C), anti -outer membrane porin C (anti-OmpC), anti-Cbirl flagellin and anti-12 antibody, and anti -neutrophil cytoplasmic autoantibodies (pANCA). In some instances, the association between a GPR35 SNP and associated serological marker with an inflammatory disease or condition disclosed herein is stronger than the association between the GPR35 SNP alone. In some instances, the presence of a serological marker in combination with the GPR35 SNP is predictive of the inflammatory disease or condition.

Table 1. GPR35 Single Nucleotide Polymorphisms

[0085] In some embodiments, if 0R<1, the minor allele correlates to a reduced risk of a patient exhibiting a corresponding phenotype. In some embodiments, if OR>l, the minor allele correlates to an increased risk of a patient exhibiting a corresponding phenotype.

[0086] In some instances, the SNP occurs in an expression quantitative trait locus (eQTL).

Expression quantitative trait loci are genomic loci that affect expression of an mRNA or protein. In some instances, a SNP in an eQTL results in increased GPR35 expression. In some instances, a SNP in an eQTL results in decreased GPR35 expression. In some instances, the eQTL is a local eQTL, e.g., within the gene locus. In some instances, the eQTL is a distant eQTL, e.g., outside of the gene locus. In some instances, the eQTL is on a different chromosome than the GPR35 locus, referred to herein as a trans eQTL. In some instances, the eQTL is on the same chromosome as the GPR35 locus, referred to herein as a cis eQTL. In some instances, the eQTL is tissue-independent. In some instances, the eQTL is tissue-dependent. In some instances, methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of rectum tissue. In some instances, methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of anal tissue. In some instances, methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of colon tissue. In some instances, methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of intestinal tissue. In some instances, methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of stomach tissue. In some instances, methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of esophageal tissue. QTL mapping may be performed by analysis of variance (ANOVA), standard interval mapping, composite interval mapping, and family -based pedigree mapping.

[0087] The combination of an eQTL and an association between a SNP and an IBD may allow one to determine how gene expression is related to risk of disease. By way of non -limiting example, rs3749171 has both eQTL and an association with an IBD. eQTL shows that the minor allele codes for upregulation of the GPR35 mRNA in small bowel tissue and the association shows that minor allele is a risk for UC, IBD and CD. In other cases the minor allele may code for upregulation of the gene but the major allele might be the risk allele.

[0088] Methods of Treating of Inflammatory Diseases or Conditions

[0089] Disclosed herein, in some embodiments, are methods of treating an inflammatory disease or condition, or a symptom of the inflammatory disease or condition, in a subject, comprising administrating of therapeutic effective amount of one or more therapeutic agents to the subject. In some embodiments, the one or more therapeutic agents is administered to the subject alone (e.g., standalone therapy). In some embodiments, the one or more therapeutic agents is administered in combination with an additional agent. In some embodiments, the therapeutic agent is a first-line therapy for the disease or condition. In some embodiments, the therapeutic agent is a second-line, third-line, or fourth-line therapy, for the disease or condition.

[0090] In some embodiments, the subject to be treated with the therapeutic agent is selected for treatment based on a presence of one or more single nucleotide polymorphisms (SNPs) detected in a sample obtained from the subject. In some embodiments, the one or more SNPs comprises a SNP at the GPR35 gene, or genetic locus. In some embodiments, the one or more SNPs comprises a SNP in linkage disequilibrium with rs3749171 as determined by an r² of at least about 0.70, about 0.75, about 0.80, about 0.85, about 0.85, about 0.90, or about 1.0. In some embodiments, the SNP comprises one or more of rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402, rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl l6803432, rsl3016146, rsl 15661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl l33726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, and/or or rs78571781. In some embodiments, the SNP comprises a risk allele provided in [brackets] within any one or SEQ ID NOS: 1-31 shown in Table 30. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, a GPR35 genotype comprises the SNP. In some embodiments, the SNP is detected in a biological sample obtained from the subject using one or more of the methods of detection described herein.

[0091] Therapeutic Agents

[0092] Compositions, kits and methods disclosed herein may comprise a therapeutic agent or use thereof. Thetherapeutic agents disclosed herein are useful for the treatment of the inflammatory diseases or conditions, or symptoms of the inflammatory diseases or conditions disclosed herein. Non limiting examples of classes of therapeutic agents used to treat the inflammatory diseases or conditions disclosed herein include anti-inflammatory mediators ( e.g small molecule and large molecule), steroids, and tumor necrosis factor (TNF) inhibitors. Non-limiting examples of therapeutic agents used to treat IBD include azathioprine, methotrexate, 6-mercaptopurine, prednisone, mesalazinc. and budesonide.

[0093] Methods disclosed herein that comprise the use of a therapeutic agent may substitute or supplement the use of the therapeutic agent with a nutritional-based therapy, nature-based therapy, or diet-based therapy. For example, subjects with anemia may benefit from parenteral iron

supplementation. In some instances, methods comprise administering a B vitamin, fat-soluble vitamin, an essential fatty acid, magnesium, zin, selenium, or a combination thereof. In some instances, methods comprise administering Plantago ovata, curcumin, wormwood, or a combination thereof. In some instances, methods comprise administering an antibiotic. Conversely, in some instances, methods comprise administering a microbe, e.g., a fecal microbiota transplant.

[0094] Compositions, kits and methods disclosed herein may comprise and/or utilize a therapeutic agent or use thereof, wherein the therapeutic agent is effective to modify expression and/or activity of GPR35 (e.g., modulator of GPR35). Therapeutic agents that modify expression and/or activity of GPR35 may also be referred to herein as GPR35 -targeting agents. Alternatively or additionally, compositions, kits and methods disclosed herein may comprise and/or utilize a therapeutic agent or use thereof, wherein the therapeutic agent modifies expression and/or activity of a protein that functions upstream or downstream of a pathway that involves GPR35. In some embodiments, the modulator of GPR35 is effective to increase or activate the activity or expression of GPR35 in the subject (e.g., agonist or partial agonist). In some embodiments, the modulator of GPR35 is effective to decrease or reduce the activity or expression of GPR35 (e.g., antagonist or partial antagonist).

[0095] In some instances, the therapeutic agent is an antagonist of GPR35. In some instances, the antagonist acts as an inverse agonist. Non-limiting examples of inverse agonists are ML145 and ML144. In some instances, the therapeutic agent is an allosteric modulator of GPR35. Methods disclosed herein may comprise administering GPR35 -targeting agents alone. In other instances, methods disclosed herein may comprise administering GPR35 -targeting agents along with another therapeutic agent disclosed herein, a nutritional -based therapy, a nature-based therapy, a diet-based therapy, or a combination thereof.

[0096] In some instances, the subject has a SNP that is associated with, or causes, an increased expression of GPR35. In some instances, the subject has a SNP that is associated with, or causes increased activity of GPR35. In some instances, the SNP is associated with, or causes and increase expression of GPR35. In some instances, the SNP is associated with, or causes an increase activity of GPR35. In these instances, it may be suitable to use a GPR35 antagonist to bring GPR35 activity back to a normal level, e.g., that of a person without the IBD of the subject.

[0097] In some instances, the subject has a SNP that is associated with, or causes decreased expression of GPR35. In some instances, the subject has a SNP is associated with, or causes, decreased activity of GPR35. In some instances, the SNP is associated with, or causes, a decrease in expression of GPR35. In some instances, the SNP is associated with, or causes, decreased activity of GPR35. In these instances, it may be suitable to use a GPR35 agonist to bring GPR35 activity back to a normal level, e.g., that of a person without the IBD of the subject.

[0098] In some instances, the therapeutic agent is a small molecule drag. By way of non-limiting example, a small molecule drug may be a chemical compound. In some cases, a small molecule has a molecular weight less than about 1,000 Da, or less than about 900 Da, or less than about 800 Da. In some cases, a small molecule has a molecular weight from about 50 Da to about 1,000 Da. In some instances, the therapeutic agent is a large molecule drug. Large molecule drugs generally comprise a peptide or nucleic acid. By way of non-limiting example, the large molecule drug may comprise an antibody or antigen binding antibody fragment. In some instances, the therapeutic agent comprises a small molecule and a large molecule. By way of non-limiting example, the therapeutic agent may comprise an antibody-drug conjugate.

[0099] In some instances, the therapeutic agent is a small molecule that binds GPR35. In some instances, the small molecule that binds GPR35 is a GPR35 agonist. In some instances, the small molecule that binds GPR35 is a GPR35 partial agonist. In some instances, the small molecule that binds GPR35 is a GPR35 antagonist. In some instances, the small molecule that binds GPR35 is a GPR35 partial agonist.

[00100] In some instances, the small molecule that binds GPR35 is a compound of Formula (I):

each R⁵ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -

phenyl, -Ci_₆alkyl-phenyl, C_{2 9}heterocycloalkyl, and Ci_₉heteroaryl; wherein phenyl, -C i 6alkyl -phenyl, and C _{| 9}helcroaryl are optionally substituted with one, two, or three groups independently selected from halogen, Ci_₆alkyl, C _| Jialoalkyl. C_3-8cycloalkyl, and C _ 9heterocycloalkyl; and wherein C₂_9heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, Ci_₆alkyl, Ci_₆haloalkyl, and oxo;

each R⁷ is independently selected from H and Ci_₆alkyl;

each R⁸ is independently selected from halogen, -OH, -OR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -

₍haloalkvl H. C_3-8cycloalkyl, -Ci_₆alkyl-C_3-gcycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.

9heterocycloalkyl, and C _|-9hctcroaryl: wherein phenyl, -Ci_₆alkyl-phenyl, and Ci_₉heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and C_2-9heterocycloalkyl; and wherein C₂_

9heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, C _|_„alkyl. Ci_₆haloalkyl, and oxo;

each R⁹ is independently selected from C _|.(, alkyl. Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein C _|-f alkyl, phenyl, -Ci__salkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, -N(Rⁿ)₂, and -C(0)0R¹²; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C _{| (},alkyl . oxo, and -C(0)0H; each R¹¹ is independently selected from H and Ci_₆alkyl;

R¹² is independently selected from H and Ci_₆alkyl;

R¹³ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci-₆alkyl-C_3-8cycloalkyl, phenyl, - Ci_₆alkyl -phenyl, and C_2.9heteroaryl;

each R¹⁴ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ gcycloalkyl, phenyl, -C _| alkyl-phenyl. C_{2 9}heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_{2 9}heteroaryl, and -C _| ,alkyl-C_{2 9}helcroaryl:

n is 0, 1, 2, or 3;

p is 0, 1, 2, 3, 4, or 5; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00101] In some instances, the small molecule that binds GPR35 is a compound of Formula (II):

Formula (II);

wherein:

X¹, X², Y¹, and Y² are independently selected from O, NR¹³, and C(R¹⁴)₂;

R¹ and R² are independently selected from -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -

R³ is selected from -OH

C(0)R⁹, -C(0)OR¹⁰

NR¹⁰C(O)R⁹, -NR¹⁰

6alkenyl, C_2-6alkynyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and -Ci.₆alkyl-C_3.8cycloalkyl;

each R⁴ and R⁵ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, CY_f.alkyl -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, C_|_„haloalkyl. C_3-8cycloalkyl, and - Ci-₆alkyl -C_3.8cycloalkyl ;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci__salkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-gcycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C₂_9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, C _| alkyl. and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ r, alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and Ci_₆alkyl;

each R¹² is independently selected from H and Ci_₆alkyl;

each R¹³ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-gcycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl;

each R¹⁴ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-gcycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C₂_9heterocycloalkyl, -Ci_6alkyl-C₂-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C₂_9heteroaryl;

m is 1, 2, 3, 4, or 5;

n is 1, 2, 3, 4, or 5;

p is 0, 1, 2, or 3; and

q is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

[00102] In some instances, the small molecule that binds GPR35 is a compound of Formula (III):

Formula (III);

wherein:

X¹ and X² are independently selected from O, NR¹³, and C(R¹⁴)₂;

R¹ and R² are independently selected from -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, - C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -

NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, Ci_₆alkyl, -C ,alkvl-OH. -Ci_₆alkyl-OR⁹, and -Ci_₆alkyl-

N(R¹⁰)₂;

R³ and R⁴ are independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹,

and -

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_{2 g}hctcroaryk and -Ci_₆alkyl-C_{2 9}heteroaryl, wherein C _{| (} alkyl phenyl, -C _{| '}.alkyl-pkcnyl. -C 6alkyl-C_2-9heterocycloalkyl, C_{2 9}heteroaryl, and -C_|„alkyl-C_{2 9}hetcroaryl are optionally substituted with one or two groups independently selected from CV₆alkyl, -OR¹¹, -N(Rⁿ)₂, C 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²,

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -CY_<, alkyl -CY scycloalkyl, phenyl, -CY₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C _-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, CY₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from CY r.alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CYr.alk l:

each R¹² is independently selected from H and CYr.alkyl:

each R¹³ is independently selected from H, CY₆alkyl, CY₆haloalkyl, C_3-8Cycloalkyl, -CYr.alkyl -CY scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl; and

each R¹⁴ is independently selected from H, CY₆alkyl, CY₆haloalkyl, C_3-8cycloalkyl, -CY₆alkyl-C₃_ scycloalkyl, phenyl, -CY₆alkyl-phenyl, C_2.9heterocycloalkyl, -CY₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -CY₆alkyl-C_2-9heteroaryl;

or a pharmaceutically acceptable salt or solvate thereof.

[00103] In some instances, the small molecule that binds GPR35 is a compound of Formula (IV):

Formula (IV);

wherein:

X¹ and X² are independently selected from 0, NR¹³, and C(R¹⁴)₂;

R³ and R⁴ are independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, CY₍, alkyl. -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -CY₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, CY₆haloalkyl, C_3-8cycloalkyl, and - C _{| (},alkyl -CYgCydoalkyl ;

each R⁹ is independently selected from C _|„alkyl. C_{| (},haloalkyl. C_{3 g}cycloalkyl, -CY₆alkyl-CY gcycloalkyl, phenyl, -C _| alkyl-phenyl. C_{2 9}heterocycloalkyl, -CY₆alkyl-CY₉heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl, wherein CY₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-CY₉heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl are optionally substituted with one or two groups independently selected from CY₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, CY₆alkyl, CY₆haloalkyl, C_3-8cycloalkyl, -CY_<, alkyl -CY gcycloalkyl, phenyl, -CY₆alkyl-phenyl, and C_2-9heteroaryl, wherein CY₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C _-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from CY ( alk l oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CY₍alk\i:

each R¹² is independently selected from H and CY₍ alkvl:

each R¹³ is independently selected from H, CY₆alkyl, CY₆haloalkyl, C_3-8cycloalkyl, -CY, alkyl -CY gcycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl; and

each R¹⁴ is independently selected from H, CY₆alkyl, CY₆haloalkyl, C_3-8cycloalkyl, -Ci_₍,alkyl-C₃_ gcycloalkyl, phenyl, -CY₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl;

or a pharmaceutically acceptable salt or solvate thereof.

[00104] In some instances, the small molecule that binds GPR35 is a compound of Formula (V):

Formula (V);

wherein:

R¹ and R² are independently selected from H, CY₆alkyl, CY₆haloalkyl, C_3.gCycloalkyl, -CY₆alkyl- C_3.gCycloalkyl, phenyl, -CYr, alkyl -phenyl, and C₂-9heteroaryl; each R³ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and - C_{| (},alkvl -C_{3 g}cycloalkyl ;

each R⁹ is independently selected from C _|„alkyL CV₆haloalkyl, C_{3 8}cycloalkyl, -Ci_₆alkyl-C₃_ gcycloalkyl, phenyl, -C _| lkyl-phenyl. C_{2 9}heterocycloalkyl, -Ci_₆alkyl-C_{2 9}heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3.8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C _-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ r.alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CYr.alkyl:

each R¹² is independently selected from H and CY₆alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00105] In some instances, the small molecule that binds GPR35 is a compound of Formula (VI):

Formula (VI);

wherein:

X is selected from O, NR¹³, and C(R¹⁴)₂;

R¹ and R² are independently selected from -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, - C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, - NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, Ci_₆alkyl, -Ci_₆alkyl-OH, -Ci_₆alkyl-OR⁹, and -Ci_₆alkyl- N(R¹⁰)₂; R³ and R⁴ are independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and - C_{| (},alkvl -C_{3 8}cycloalkyl ;

each R⁵ and each R⁶ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, - S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, - C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C , alkyl. - Ci_₆alkyl-OH, -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, CV„haloalk\ l. C₃_ scycloalkyl, and -Ci_₆alkyl-C_3-8cycloalkyl;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl, wherein C .alkyl. phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -CV„alkyl-C₂__<,hctcroaiyl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8Cyeloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CVi, alkyl:

each R¹² is independently selected from H and CYi.alkyl:

R¹³ is selected from H, C_{| -(}, alkyl. Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C_3-8cycloalkyl, phenyl, - Ci_₆alkyl -phenyl, and C_2-9heteroaryl;

each R¹⁴ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -C_|_„alkyl-C\_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -C m,, alkyl -C_2-9hcterocycloalkyl. C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00106] In some instances, the small molecule that binds GPR35 is a compound of Formula (VII):

Formula (VII);

R¹ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C_3.8cycloalkyl, phenyl, -

8cycloalkyl;

each R³ and each R⁴ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, - S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, - C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C, alkyl. - C_{| (},alkyl-OH. -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_{2 6}alkenyl, C_{2 6}alkynyl, Ci_₆haloalkyl, C₃ ₈cycloalkyl, and -Ci_₆alkyl-C_3.8cycloalkyl;

each R⁹ is independently selected from CY,, alkyl. Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C₂_9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from C , alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, CY₈cycloalkyl. -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ (alkyl. oxo, and -C(0)0H;

each R¹¹ is independently selected from H and Ci_₆alkyl;

each R¹² is independently selected from H and Ci_₆alkyl;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof. [00107] In some instances, the small molecule that binds GPR35 is a compound of Formula (VIII):

Formula (VIII);

wherein:

X is selected from -0-, -S-, and -S0₂-;

R¹ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C_3-8cycloalkyl, phenyl, - Ci_₆alkyl -phenyl, and C_2-9heteroaryl;

each R² and each R³ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -

R⁴ is selected from

R⁵ i

8cycloalkyl;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.gcycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_{3 8}cycloalkyl, -C _| alkyl -C_’, scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_{2 9}heteroaryl, wherein C _| -.alkyl phenyl, -C i 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and Ci_₆alkyl;

each R¹² is independently selected from H and C _| alkyl:

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

[00108] In some instances, the small molecule that binds GPR35 is a compound of Formula (IX):

Formula (IX);

wherein:

X is selected from -0- and -S-;

R¹ is selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹,

scycloalkyl;

R² is selected from

each R³ is independently selected from halogen, -CN, -OH, N0₂, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-gcycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_{2 9}heteroaryl are optionally substituted with one or two groups independently selected from halogen, C_| alkyl and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ (alkyl. oxo, and -C(0)0H;

each R¹¹ is independently selected from H and Ci_₆alkyl;

each R¹² is independently selected from H and Ci_₆alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00109] In some instances, the small molecule that binds GPR35 is a compound of Formula (X):

Formula (X);

wherein:

R¹ is selected from

each R² is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -

each R³ is independently selected from H, halogen, -CN, -OH, N0₂, -OR⁹, -SR⁹, -N(R¹⁰)₂, - S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, - C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, - C , _falkyl-OH, -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_{2 6}alkenyl, C_{2 6}alkynyl, C _|„haloalkyL C₃ icycloalkyl, and -Ci_₆alkyl-C_3.8cycloalkyl; each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci.₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C₂-9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, C 6 alkyl, C_{3 8}cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, C_{| (}haloalkyf C_{3 g}cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C _-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ r.alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and C’ , alkyl:

each R¹² is independently selected from H and Ci_₆alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00110] In some instances, the small molecule that binds GPR35 is a compound of Formula (XI):

Formula (XI);

wherein:

X is selected from -0-, -S-, and -S0₂-;

R¹ is selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, - NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C , alkyl. -Ci_₆alkyl-OH, -Ci_₆alkyl-OR⁹, - Ci_₆alkyl-N(R¹⁰)₂, C_2.6alkenyl, C_2-6alkynyl, Ci-ehaloalkyl, C_3.8cycloalkyl, and -Ci_₆alkyl-C₃_ scycloalkyl;

each R² and each R³ is independently selected from halogen, -CN, -OH,

S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹

C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -N

Ci_₆alkyl-OH, -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6al

scycloalkyl, and -Ci_₆alkyl-C_3.8cycloalkyl; each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci.₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C₂-9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, C 6 alkyl, C_{3 8}cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, C_{| (}haloalkyl. C_{3 8}cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ r.alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and C’ , alkyl:

each R¹² is independently selected from H and Ci_₆alkyl;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00111] In some instances, the small molecule that binds GPR35 is a compound of Formula (XII):

Formula (XII);

wherein:

X is selected from -0-, -S-, -NR¹³-, and -C(R¹⁴)₂-;

each R¹ is independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, . 6alkyl, -Ci_₆alkyl-OH, -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2-6alkynyl, .

r.haloalkyl, C_3-8cycloalkyl, and -Ci_₆alkyl-C_3-8cycloalkyl;

R² is selected from H and Ci_₆alkyl;

each R³ and each R⁴ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, - S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, - C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, - Ci-₆alkyl-OH, -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, Ci_₆haloalkyl, C₃_ 8cycloalkyl, and -Ci_₆alkyl-C_3.8cycloalkyl; each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci.₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C₂-9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, C 6 alkyl, C_{3 8}cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, C_{| (}haloalkyl. C_{3 g}cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ i.alkyt. oxo, and -C(0)0H;

each R¹¹ is independently selected from H and C’ .alkyl:

each R¹² is independently selected from H and Ci_₆alkyl;

R¹³ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci.₆alkyl-C_3.8Cycloalkyl, phenyl, - Ci_₆alkyl -phenyl, and C_2.9heteroaryl;

R¹⁴ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci.₆alkyl-C3_₈cycloalkyl, phenyl, - Ci-₆alkyl-phenyl, C_2-9heterocycloalkyl, -Ci_₆alkyl-C₂_9heterocycloalkyl, C_2-9heteroaryl, and - Ci-₆alkyl-C₂_9heteroaryl;

p is 0, 1, 2, 3, or 4; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00112] In some instances, the small molecule that binds GPR35 is a compound of Formula (XIII):

Formula (XIII);

wherein:

X¹ and X² are independently -0-, -S-, or -NR¹³-;

R¹ is selected from

R² i

gcycloalkyl;

each R³ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, CiJialoalkyl. C_3-8cycloalkyl, and - Ci_₆alkyl -C_3.8cycloalkyl ;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2-9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8Cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C₂-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;

p is 0, 1 or 2;

or a pharmaceutically acceptable salt or solvate thereof.

[00113] In some instances, the small molecule that binds GPR35 is a compound of Formula (XIV):

Formula (XIV);

wherein: R¹ and R² are independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C , alkyl. -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and - Ci-₆alkyl -C_{3 8}cycloalkyl ;

each R³ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C _M, alkyl. -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, CiJialoalkyl. C_3-8cycloalkyl, and - Ci_₆alkyl -C_3.8cycloalkyl ;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8Cyeloalkyl, -C m₍, alkyl -CN scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CY alkyl:

each R¹² is independently selected from H and CY₍alkyl: and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00114] In some instances, the small molecule that binds GPR35 is a compound of Formula (XV):

Formula (XV);

wherein:

X is selected from -0-, -S-, and -S0₂-;

Y is N or CR²;

each R³ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, -C^alkyl-OH, - Ci-₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2-6alkynyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and - Ci_₆alkyl -C_3.8cycloalkyl ;

each R⁹ is independently selected from C , alkyl. Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl, wherein CV_(,alk\ l. phenyl, -CV,alk_} l-phcn_} l. -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -C_M6alkyl-C _-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3.8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -C _|-(, alkyl -C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CY₍, alkyl:

each R¹² is independently selected from H and CY₍, alkyl: and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00115] In some instances, the small molecule that binds GPR35 is a compound of Formula (XVI):

Formula (XVI);

wherein: X is selected from -0-, -S-, and -NR -;

R¹ is selected from

each R² and each R⁷ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, - S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, - C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, Ci_₆alkyl, - Ci_₆alkyl-OH, -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, Ci_₆haloalkyl, C₃_ scycloalkyl, and -Ci-₆alkyl-C_3.8cycloalkyl;

R³ and R⁴ are independently selected from H and Ci_₆alkyl;

R⁵ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C_3-8cycloalkyl, phenyl, -

scycloalkyl;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci__salkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C i (alkyl. oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CV₍, alkyl:

each R¹² is independently selected from H and C’ , alkyl:

R¹³ is selected from H, C’ , alkyl. C haloalkyl. C_3.8cycloalkyl, -Ci_₆alkyl-C_3.8cycloalkyl, phenyl, - Ci-ealkyl -phenyl, and C_2.9heteroaryl; p is 0, 1, 2, or 3; and

q is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

[00116] In some instances, the small molecule that binds GPR35 is a compound of Formula (XVII):

Formula (XVII);

wherein:

X is selected from -0-, -S-, and -S0₂-;

R¹ is selected from

each R⁹ is independently selected from C i_,,alkyl. Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci.₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -C _m(, alkyl -C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CY₍alkyl:

each R¹² is independently selected from H and CY₍alkyl:

p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00117] In some instances, the small molecule that binds GPR35 is a compound of Formula (XVIII):

Formula (XVIII);

wherein:

R¹ is selected from

R² is independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -

each R³ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, Ci-ealkyl, -Ci_₆alkyl-OH, - and -

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)OR¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ 6alkyl, oxo, and -C(0)OH; each R¹¹ is independently selected from H and Ci_₆alkyl;

each R¹² is independently selected from H and C _|-f, alkyl: and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00118] In some instances, the small molecule that binds GPR35 is a compound of Formula (XIX):

Formula (XIX);

wherein:

X is selected from -0-, -S-, and -NR¹³-;

R¹ is selected from H and Ci_₆alkyl;

R² is independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C , alkyl. -C ,., alkyl -Oi l. - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and - Ci_₆alkyl -C_3-8cycloalkyl ;

R³ i

scycloalkyl;

each R⁴ is independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C _{l (},alky l. -C alkyl-OH. - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2.(, alkenyl. C_2.6alkynyl, C _|.„haloalkyl. C_3-8cycloalkyl, and - Ci-₆alkyl -C_3.8cycloalkyl ;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein C _|.(alkyl. phenyl, -Ci__salkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and C _| alkyl:

each R¹² is independently selected from H and C _| alkyl:

R¹³ is selected from H, C_| alkyl. Ci_₆haloalkyl, C_{3 8}cycloalkyl, -C_{| f}alkyl-C _xcycloalkyl, phenyl, - Ci_₆alkyl -phenyl, and C_2-9heteroaryl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00119] In some instances, the small molecule that binds GPR35 is a compound of Formula (XX):

Formula (XX);

wherein:

X is selected from -O- and -C(R¹⁴)₂-;

R¹ is selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, - NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C,.,, alkyl. -C,.,, alkyl -OH. -C ,.,, alkyl -OR⁹. - Ci-₆alkyl-N(R¹⁰)₂, C_2.6alkenyl, C_2-6alkynyl, CiJialoalkvl. C_3.8cycloalkyl, and -C_{| 3}, alkyl-C 8cycloalkyl;

R² is selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, - NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, O_m(, alkyl. -C,., alkyl -OH. -C_{l 3}, alkyl -OR⁹. - Ci_₆alkyl-N(R¹⁰)₂, C_2.6alkenyl, C_2-6alkynyl, Ci^haloalkyl, C_3-gcycloalkyl, and -C_{| 3},alk\l-C «cycloalkyl:

each R³ and each R⁴ is selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C^alkyl, -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and - Ci_₆alkyl -C_3.8cycloalkyl ; each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci.₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C₂-9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, C 6 alkyl, C_{3 8}cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, C_{| (}haloalkyl. C_{3 g}cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ r.alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and C’ , alkyl:

each R¹² is independently selected from H and Ci_₆alkyl;

each R¹⁴ is independently selected from H, halogen, C _|-<, alkyl. Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_ 6alkyl-C_3.8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2-9heterocycloalkyl, -Ci_₆alkyl-C₂- gheterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl; and

or a pharmaceutically acceptable salt or solvate thereof.

[00120] In some instances, the small molecule that binds GPR35 is a compound of Formula (XXI):

Formula (XXI);

wherein:

X¹ and X² are independently selected from -0- and -S-;

each R¹ and each R² are independently selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, - S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, - C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, - Ci_₆alkyl-OH, -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2-6alkynyl, Ci_₆haloalkyl, C₃_ 8cycloalkyl, and -Ci_₆alkyl-C_3.8cycloalkyl;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C₂-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-gcycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_{2 9}lictcroaiyl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C₃_ (alkyl. oxo, and -C(0)0H;

each R¹¹ is independently selected from H and Ci_₆alkyl;

each R¹² is independently selected from H and Ci_₆alkyl;

R¹³ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C_3-8cycloalkyl, phenyl, - Ci_₆alkyl -phenyl, and C_2-9heteroaryl;

p is 0, 1, 2, or 3;

q is 0, 1, 2, or 3; and

or a pharmaceutically acceptable salt or solvate thereof.

[00121] In some instances, the small molecule that binds GPR35 is a compound of Formula (XXII):

Formula (XXII);

wherein:

X is selected from -0- and -S-;

R¹, R², and R³ are independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, - S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, - C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, -

Ci-₆alkyl-OH, -Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, C _|-(haloalkyl, C_; scycloalkyl, and -Ci.₆alkyl-C_3.gcycloalkyl;

each R⁴ is selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -

NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, - NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C_1-6alkyl, -C ^alkyl-OH. -C _Ualkyl-OR\ - Ci_₆alkyl-N(R¹⁰)₂, C_2.6alkenyl, C_2-6alkynyl, C_| Jialoalkyl. C_3.8cycloalkyl, and -Ci_₆alkyl-C₃_ scycloalkyl;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_{2 9}heteroaryl, and -C _| ,alkyl-C₂ dictcroaryk wherein C) ₍ alkyl phenyl, -Ci_₆alkyl-phenyl, -C ₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, CY 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-gcycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -C _| alkyl-phenyl. and C_{2 r},hctcroaryl. wherein C _| -.alkyl phenyl, -C i 6alkyl -phenyl, and C_{2 9}heteroaryl are optionally substituted with one or two groups independently selected from halogen, C _| alkyl. and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from CY 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and Ci_₆alkyl;

each R¹² is independently selected from H and Ci_₆alkyl; and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00122] In some instances, the small molecule that binds GPR35 is a compound of Formula (XXIII):

Formula (XXIII);

wherein:

each X is independently selected from -O- and -S-;

R¹ is selected from

each R² is selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -

NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, - NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C , alkyl. -C , alkyl -OI I. -Ci_₆alkyl-OR⁹, - Ci_₆alkyl-N(R¹⁰)₂, C_2.6alkenyl, C_2-6alkynyl, Ci-ehaloalkyl, C_3.8cycloalkyl, and -Ci-ealkyl-CY scycloalkyl;

R³ is selected from H, Ci_₆alkyl, CY₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C_3-8cycloalkyl, phenyl, - Ci_₆alkyl -phenyl, and C_2.9heteroaryl; each R⁴ and each R⁵ are independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂,

gcycloalkyl, and -C_{| f}alkyl-C_{3 g}cycloalkyl :

R⁶ is selected from C_{3 g}cycloalkyl, C_{2 9}heterocycloalkyl, C_{2 9}heteroaryl, and phenyl, wherein C gcycloalkyl, C_{2 9}heterocycloalkyl, C_{2 9}heteroaryl, and phenyl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(R^U)₂, CY_f, alkyl, C₃_ gcycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ gcycloalkyl, phenyl, -CY₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl, wherein CY_f, alkyl, phenyl, -CY₆alkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C₃-gcycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -C i__(<alk\ l-C₃_ gcycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CY₍alkyl:

each R¹² is independently selected from H and CY alkyl: and

p is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00123] In some instances, the small molecule that binds GPR35 is a compound of Formula (XXIV):

Formula (XXIV);

wherein:

X is selected from -O- and -S-; R¹ is selected from

each R² is selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -

NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -0C(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, - NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, Ci-ealkyl, -Ci_₆alkyl-OH, -Ci_₆alkyl-OR⁹, - Ci-₆alkyl-N(R¹⁰)₂, C_2.6alkenyl, C_2-6alkynyl, Ci^haloalkyl, C_3.8cycloalkyl, and -C ,alkvl-CY scycloalkyl;

each R³ is selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -

scycloalkyl;

R⁴ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, and C_3-8cycloalkyl;

R⁵ is selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C_3.8cycloalkyl, phenyl, - Ci_₆alkyl -phenyl, and C_2.9heteroaryl;

R⁶ is independently selected from H, Ci_₆alkyl, C_{| 3},haloalkyl. C_3-8cycloalkyl, -Ci_₆alkyl-C₃_

8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)0R¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C_2-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from CY (alkyl. oxo, and -C(0)0H;

each R¹¹ is independently selected from H and CY₍, alkyl;

each R¹² is independently selected from H and C , alkyl: and

p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.

[00124] In some instances, the small molecule that binds GPR35 is a compound of Formula (XXV):

Formula (XXV);

wherein:

X is selected from CR² or N;

R¹ is selected from C_3.8cycloalkyl, C₂-9heterocycloalkyl, C₂-9heteroaryl, and phenyl, wherein C₃_ 8cycloalkyl, C_2-9heterocycloalkyl, C_2-9heteroaryl, and phenyl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(R^U)₂, CY_f, alkyl, C₃_ scycloalkyl, -C(0)R¹², and -C(0)OR¹²;

each R² and each R⁶ is selected from halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, - S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C , alkyl. -C^alkyl-OH, - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, CY„haloalkyl. C_3-8cycloalkyl, and - Ci.₆alkyl -C_3-8cycloalkyl ;

R³ and R⁴ are independently selected from H, halogen, -CN, -OH, -OR⁹, -SR⁹, -N(R¹⁰)₂, -S(0)R⁹, -S(0)₂R⁹, -NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, - OC(O)N(R¹⁰)₂, -NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, Ci-ealkyl, -C’u.alkvl-OH. - Ci_₆alkyl-OR⁹, -Ci_₆alkyl-N(R¹⁰)₂, C_2-6alkenyl, C_2.6alkynyl, Ci_₆haloalkyl, C_3-8cycloalkyl, and - Ci-₆alkyl -C_3.8cycloalkyl ;

each

- Ci_₆alkyl -C_3.8cycloalkyl ;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ 8cycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_₆alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl, wherein C _|-(alkyl. phenyl, -Ci__salkyl-phenyl, -Ci_ 6alkyl-C_2.9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C_2-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)OR¹²; each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C₂-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C₂-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C i 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and Ci_₆alkyl;

each R¹² is independently selected from H and C’ , alkyl;

p is 0, 1, 2, 3, 4, 5, or 6; and

q is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt or solvate thereof.

[00125] In some instances, the small molecule that binds GPR35 is a compound of Formula (XXVI):

R¹

Fo U- (X<^RXY⁾- wherein:

R¹ is selected from

NHS(0)₂R⁹, -S(O)₂N(R¹⁰)₂, -C(0)R⁹, -C(0)OR¹⁰, -OC(0)R⁹, -C(O)N(R¹⁰)₂, -OC(O)N(R¹⁰)₂, - NR¹⁰C(O)N(R¹⁰)₂, -NR¹⁰C(O)R⁹, -NR¹⁰C(O)OR⁹, C , alkyl. -C , alkyl -Oi l. -C ,.₍,alk>l-OR⁹. - Ci.₆alkyl-N(R¹⁰)₂, C_2.6alkenyl, C_2-6alkynyl, Ci^haloalkyl, C_3.8cycloalkyl, and -C ,alkyl-C₃_ scycloalkyl;

each R⁹ is independently selected from Ci_₆alkyl, Ci_₆haloalkyl, C_3.8cycloalkyl, -Ci_₆alkyl-C₃_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, C_2.9heterocycloalkyl, -Ci_6alkyl-C₂_9heterocycloalkyl, C₂-9heteroaryl, and -Ci_₆alkyl-C₂-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_₆alkyl-phenyl, -Ci_ 6alkyl-C_2-9heterocycloalkyl, C_2.9heteroaryl, and -Ci_₆alkyl-C _-9heteroaryl are optionally substituted with one or two groups independently selected from Ci_₆alkyl, -OR¹¹, -N(Rⁿ)₂, Ci_ 6 alkyl, C_3-8cycloalkyl, -C(0)R¹², and -C(0)OR¹²;

each R¹⁰ is independently selected from H, Ci_₆alkyl, Ci_₆haloalkyl, C_3-8cycloalkyl, -O_m(, alkyl -C _;_ scycloalkyl, phenyl, -Ci_₆alkyl-phenyl, and C_2-9heteroaryl, wherein Ci_₆alkyl, phenyl, -Ci_ ₆alkyl -phenyl, and C₂-9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_₆alkyl, and -N(Rⁿ)₂; or two R¹⁰ and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;

each R¹¹ is independently selected from H and C _{| f}, alkyl:

each R¹² is independently selected from H and C _{| f}, alkyl

p is 0, 1, 2, 3, or 4; and

or a pharmaceutically acceptable salt or solvate thereof.

[00126] In some instances, the small molecule that binds GPR35 is selected from zaprinast, lodoxamide, bufrolin, TC-G 1001, nedocromil, PSB-13253, 6-bromo-7-hydroxy-8-nitro-3-(lH- tetrazol-5-yl)-2H-chromen-2-one, 6-bromo-7-hydroxy-8-nitro-2-oxo-2H-chromene-3-carboxylic acid, 7-deshydroxypyrogallin-4-carboxylic acid (DCA), morin, cromolyn, T₃, reverse T₃ YE-210, cromoglicic acid, nedocromil, pamoic acid, and tyrphostin-51.

[00127] In some instances, the small molecule that binds GPR35 is selected from pamoic acid, amlexanox, furosemide, doxantrazole, kynurenic acid, DHICA, cyclic guanosine monophosphate (cGMP), 2,3,5-THB, ellagic acid, _. LPA species, and YE120.

[00128] In some instances, the small molecule that binds GPR35 is selected from ML-145, ML-194, and ML- 144.

[00129] In some instances, the small molecule that binds GPR35 is selected from:

[00130] In some instances, the small molecule that binds GPR35 is selected from:

[00131] In some instances, the small molecule that binds GPR35 is selected from:

[00132] In general, therapeutic agents described herein are provided in the form of a pharmaceutical composition. The pharmaceutical composition may comprise one or more pharmaceutically acceptable salts, excipients or vehicles. Pharmaceutically acceptable salts, excipients, or vehicles include, but are not limited to, carriers, excipients, diluents, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, tonicity agents, cosolvents, wetting agents, complexing agents, buffering agents, antimicrobials, and surfactants. Neutral buffered saline or saline mixed with serum albumin are exemplary appropriate carriers.

[00133] The compositions may include antioxidants such as ascorbic acid; low molecular weight polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as Tween, pluronics, or polyethylene glycol (PEG). Also by way of example, suitable tonicity enhancing agents include alkali metal halides (in some cases, preferably sodium or potassium chloride), mannitol, sorbitol, and the like. Suitable preservatives include benzalkonium chloride, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid and the like. Hydrogen peroxide also may be used as preservative. Suitable cosolvents include glycerin, propylene glycol, and PEG. Suitable complexing agents include caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxy-propyl-beta-cyclodextrin. Suitable surfactants or wetting agents include sorbitan esters, polysorbates such as polysorbate 80, tromethamine, lecithin, cholesterol, tyloxapal, and the like. The buffers may be conventional buffers such as acetate, borate, citrate, phosphate, bicarbonate, or Tris-HCl. Acetate buffer may be about pH 4-5.5, and Tris buffer may be about pH 7-8.5. Additional pharmaceutical agents are set forth in Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990.

[00134] The composition may be in liquid form, lyophilized form or freeze-dried form. The composition may include one or more lyoprotectants, excipients, surfactants, high molecular weight structural additives and/or bulking agents (see, for example, U.S. Patent Nos. 6,685,940, 6,566,329, and 6,372,716). In one embodiment, a lyoprotectant is included, which is a non-reducing sugar such as sucrose, lactose or trehalose . The amount of lyoprotectant generally included is such that, upon reconstitution, the resulting formulation will be isotonic, although hypertonic or slightly hypotonic formulations also may be suitable. In addition, the amount of lyoprotectant should be sufficient to prevent an unacceptable amount of degradation and/or aggregation of the protein upon lyophilization. Exemplary lyoprotectant concentrations for sugars (e.g., sucrose, lactose, trehalose) in the pre- lyophilized formulation are from about 10 mM to about 400 mM. In another embodiment, a surfactant is included, such as for example, nonionic surfactants and ionic surfactants such as polysorbates (e.g., polysorbate 20, polysorbate 80); poloxamers (e.g., poloxamer 188); polyethylene glycol) phenyl ethers (e.g., Triton); sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-or stearyl-sarcosine; linoleyl, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl);

myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl ofeyl-taurate; and the MONAQUAT™. series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics, PF68 etc) Exemplary amounts of surfactant that may be present in the pre-lyophilized formulation are from about 0.001-0.5%. High molecular weight structural additives (e.g., fillers, binders) may include for example, acacia, albumin, alginic acid, calcium phosphate (dibasic), cellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, dextran, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth microcrystalline cellulose, starch, and zein. Exemplary concentrations of high molecular weight structural additives are from 0.1% to 10% by weight. In other embodiments, a bulking agent (e.g., mannitol, glycine) may be included.

[00135] Compositions may be suitable for parenteral administration. Exemplary compositions are suitable for injection or infusion into an animal by any route available to the skilled worker, such as intraarticular, subcutaneous, intravenous, intramuscular, intraperitoneal, intracerebral

(intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, or intralesional routes. A parenteral formulation typically will be a sterile, pyrogen-free, isotonic aqueous solution, optionally containing pharmaceutically acceptable preservatives.

[00136] Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.

Parenteral vehicles include sodium chloride solution, Ringers' dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishes, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. See generally, Remington's Pharmaceutical Science, 16th Ed., Mack Eds., 1980, which is incorporated by reference in its entirety.

[00137] Pharmaceutical compositions described herein may be formulated for controlled or sustained delivery in a manner that provides local concentration of the product (e.g., bolus, depot effect) and/or increased stability or half-life in a particular local environment. Compositions may comprise particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. , as well as agents such as a biodegradable matrix, injectable microspheres, microcapsular particles, microcapsules, bioerodible particles beads, liposomes, and implantable delivery devices that provide for the controlled or sustained release of the active agent which then may be delivered as a depot injection. Techniques for formulating such sustained-or controlled-delivery means are known and a variety of polymers have been developed and used for the controlled release and delivery of drugs. Such polymers are typically biodegradable and biocompatible. Polymer hydrogels, including those formed by complexation of enantiomeric polymer or polypeptide segments, and hydrogels with temperature or pEI sensitive properties, may be desirable for providing drug depot effect because of the mild and aqueous conditions involved in trapping bioactive protein agents. See, for example, the description of controlled release porous polymeric microparticles for the delivery of pharmaceutical compositions in WO 93/15722. Suitable materials for this purpose include polylactides (see, e.g., U.S. Patent No. 3,773,919), polymers of poly-(a-hydroxycarboxylic acids), such as poly-D-(-)-3- hydroxybutyric acid (EP 133,988A), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman el ctl, Biopolymers, 22: 547-556 (1983)), poly(2-hydroxyethyl -methacrylate) (Langer el al, J. Biomed. Mater. Res., 15: 167-277 (1981), and Langer, Chem. Tech., 12: 98-105 (1982)), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Other biodegradable polymers include

poly(lactones), poly(acetals), poly(orthoesters), and poly(orthocarbonates). Sustained -release compositions also may include liposomes, which may be prepared by any of several methods known in the art (see, e.g., Eppstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688-92 (1985)). The carrier itself, or its degradation products, should be nontoxic in the target tissue and should not further aggravate the condition. This may be determined by routine screening in animal models of the target disorder or, if such models are unavailable, in normal animals. Microencapsulation of recombinant proteins for sustained release has been performed successfully with human growth hormone (rhGH), interferon-(rhlFN-), interleukin-2, and MN rgpl20. Johnson et al, Nat. Med., 2:795-799 (1996); Yasuda, Biomed. Then, 27: 1221-1223 (1993); Hora e? al, Bio/Technology. 8:755-758 (1990);

Cleland, "Design and Production of Single lmmunization Vaccines Using Polylactide Polyglycolide Microsphere Systems," in Vaccine Design: The Subunit and Adjuvant Approach, Powell and Newman, eds, (Plenum Press: New York, 1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Patent No. 5,654,010. The sustamed-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids may be cleared quickly within the human body. Moreover, the degradability of this polymer may be depending on its molecular weight and composition. Lewis, "Controlled release of bioactive agents from lactide/glycolide polymer," in: M. Chasin and R. Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: New York, 1990), pp. 1-41. Additional examples of sustained release compositions include, for example, EP 58,481A, U.S. Patent No. 3,887,699, EP 158,277A, Canadian Patent No. 1176565, U. Sidman et al, Biopolymers 22, 547 [1983], R. Langer et al , Chem. Tech. 12, 98 [1982], Sinha et al, J. Control. Release 90, 261 [2003], Zhu et al , Nat.

Biotechnol. 18, 24 [2000], and Dai et al, Colloids SurfB Biointerfaces 41, 117 [2005]

[00138] Bioadhesive polymers are also contemplated for use in or with compositions of the present disclosure. Bioadhesives are synthetic and naturally occurring materials able to adhere to biological substrates for extended time periods. For example, Carbopol and polycarbophil are both synthetic cross-linked derivatives of poly(acrylic acid). Bioadhesive delivery systems based on naturally occurring substances include for example hyaluronic acid, also known as hyaluronan. Hyaluronic acid is a naturally occurring mucopolysaccharide consisting of residues of D -glucuronic and N-acetyl-D- glucosamine. Hyaluronic acid is found in the extracellular tissue matrix of vertebrates, including in connective tissues, as well as in synovial fluid and in the vitreous and aqueous humor of the eye. Esterified derivatives of hyaluronic acid have been used to produce microspheres for use in delivery that are biocompatible and biodegradable (see, for example, Cortivo et al . , Biomaterials (1991) 12:727-730; EP 517,565; WO 96/29998; Ilium et al, J. Controlled Rel. (1994) 29: 133-141).

[00139] Both biodegradable and non-biodegradable polymeric matrices may be used to deliver compositions of the present disclosure, and such polymeric matrices may comprise natural or synthetic polymers. Biodegradable matrices are preferred. The period of time over which release occurs is based on selection of the polymer. Typically, release over a period ranging from between a few hours and three to twelve months is most desirable. Exemplary synthetic polymers which may be used to form the biodegradable delivery system include: polymers of lactic acid and glycolic acid, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, poly-vinyl halides,

polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyanhydrides, polyurethanes and co-polymers thereof, poly(butic acid), poly(valeric acid), alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly(methyl

methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, polyethylene glycol), polyethylene oxide), poly(ethylene terephthalate), poly(vmyl alcohols), polyvinyl acetate, poly vinyl chloride, polystyrene and polyvinylpyrrolidone. Exemplary natural polymers include alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion. The polymer optionally is in the form of a hydrogel (see, for example, WO 04/009664, WO 05/087201, Sawhney, et al, Macromolecules, 1993, 26, 581-587) that can absorb up to about 90% of its weight in water and further, optionally is cross-linked with multi-valent ions or other polymers.

[00140] Delivery systems also include non-polymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which the product is contained in a form within a matrix such as those described in U.S. Patent Nos. 4,452,775, 4,675,189 and 5,736, 152 and (b) diffusional systems in which a product permeates at a controlled rate from a polymer such as described in U.S. Patent Nos. 3,854,480, 5, 133,974 and 5,407,686. Liposomes containing the product may be prepared by methods known methods, such as for example (DE 3,218,121; Epstein et al,

Proc. Natl. Acad. Sci. USA, 82: 3688-3692 (1985); Hwang et al, Proc. Natl. Acad. Sci. USA, 77: 4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; JP 83-118008; U.S. Patent Nos. 4,485,045 and 4,544,545; and EP 102,324).

[00141] Alternatively or additionally, the compositions may be administered locally via implantation into the affected area of a membrane, sponge, or other appropriate material on to which a therapeutic agent disclosed herein has been absorbed or encapsulated. Where an implantation device is used, the device may be implanted into any suitable tissue or organ, and delivery of a therapeutic agent disclosed herein may be directly through the device via bolus, or via continuous administration, or via catheter using continuous infusion.

[00142] Formulations containing a therapeutic agent disclosed herein may be administered orally. Formulations administered in this fashion may be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. For example, a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional agents may be included to facilitate absorption of a selective binding agent. Diluents, flavorings, low melting point waxes, vegetable oils, lubncants, suspending agents, tablet disintegrating agents, and binders also may be employed.

[00143] Another preparation may involve an effective quantity of a therapeutic agent disclosed herein in a mixture with non-toxic excipients which are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions may be prepared in unit dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

[00144] Suitable and/or preferred pharmaceutical formulations may be determined in view of the present disclosure and general knowledge of formulation technology, depending upon the intended route of administration, delivery format, and desired dosage. Regardless of the manner of administration, an effective dose may be calculated according to patient body weight, body surface area, or organ size. Further refinement of the calculations for determining the appropriate dosage for treatment involving each of the formulations described herein are routinely made in the art and is within the ambit of tasks routinely performed in the art. Appropriate dosages may be ascertained through use of appropriate dose-response data. [00145] In general, methods disclosed herein comprise administering a therapeutic agent by oral administration. However, in some instances, methods comprise administering a therapeutic agent by intraperitoneal injection. In some instances, methods comprise administering a therapeutic agent in the form of an anal suppository. In some instances, methods comprise administering a therapeutic agent by intravenous (“i.v”) administration. It is conceivable that one may also administer therapeutic agents disclosed herein by other routes, such as subcutaneous injection, intramuscular injection, intradermal injection, percutaneous administration, intranasal administration, and intralymphatic injection.

[00146] Selecting and Treating a Subject

[00147] Disclosed herein, in some embodiments are methods of selecting a subject based on a presence of a single nucleotide polymorphism (SNP) in a biological sample obtained from the subject; and treating the subject with a therapeutic agent described herein (e.g., modulator of GPR35). In some embodiments, the SNP is detected using the methods of detection described herein. In some embodiments, the subject is treated in accordance with the methods of treatment described herein. In some embodiments, the SNP comprises any one, or combination of, SNPs described herein, including, but not limited to Tables 1-29.

[00148] Disclosed herein, in some aspects, are methods comprising obtaining a biological sample from a subject; assaying for the presence of at least one SNP comprising a risk allele at rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl l5684595, rsl l6803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a SNP in linkage disequilibrium (LD) therewith; and administering a therapeutic agent that modifies at least one of GPR35 expression and GPR35 activity. In some embodiments, LD is determined by an r² value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0. In some embodiments, the SNP comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, a GPR35 genotype comprises the SNP. In some embodiments, the risk allele at rsl 13435444 comprises a“G.” In some embodiments, the risk allele at rs3749171 comprises an“A.” In some embodiments, the risk allele at rs4676406 comprises an“A.”

In some embodiments, the risk allele at rs4676399 comprises a“C.” In some embodiments, the risk allele at rs2975782 comprises an“A.” In some embodiments, the risk allele at rs3749172 comprises a “C.” In some embodiments, the risk allele at rs79844648 comprises a“G.” In some embodiments, the risk allele at rs4676402 comprises a“A” In some embodiments, the risk allele at rs2975780 comprises an“A.” In some embodiments, the risk allele at rs4676396 comprises an“A.” In some embodiments, the risk allele at rs6735672 comprises an“A.” In some embodiments, the risk allele at rs34228697 comprises an“A.” In some embodiments, the risk allele at rs4676401 comprises an“A.” In some embodiments, the risk allele at rs2975786 comprises a“G.” In some embodiments, the risk allele at rs4676346 comprises a“A.” In some embodiments, the risk allele at rs6437356 comprises a “A.” In some embodiments, the risk allele at rs6745185 comprises a“C.” In some embodiments, the risk allele at rs4676407 comprises a“G.” In some embodiments, the risk allele at rs2953156 comprises a“G.” In some embodiments, the risk allele at rs4335944 comprises a“C.” In some embodiments, the risk allele at rs73999973 comprises a“A.” In some embodiments, the risk allele at rs4676410 comprises an“A.” In some embodiments, the risk allele at rs4676405 comprises a“G.” In some embodiments, the risk allele at rs2953154 comprises a“G.” In some embodiments, the risk allele at rs6732874 comprises an“A.” In some embodiments, the risk allele at rs55862430 comprises a“G.” In some embodiments, the risk allele at rsl2621598 comprises an“A.” In some embodiments, the risk allele at rs55 19442 comprises an“A.” In some embodiments, the risk allele at rs74991608 comprises an“A.” In some embodiments, the risk allele at rs34826997 comprises a“T.” In some embodiments, the risk allele at rs6437364 comprises an“A.”

[00149] Disclosed herein, in some aspects, are methods of treating an IBD in a subject, the method comprising administering a therapeutically effective amount of a therapeutic agent that targets GPR35 signaling, provided the subject has an increased or a decreased levels of GPR35 as determined by detecting in a sample obtained from the subject having a risk allele at a SNP at a GPR35 locus associated with IBD comprising rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl l33726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781 or a SNP in linkage disequilibrium therewith. In some embodiments, the SNP comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31 as shown in Table 30. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, a GPR35 genotype comprises the SNP. In some embodiments, the risk allele at rsl 13435444 comprises a“G.” In some embodiments, the risk allele at rs3749171 comprises an“A.” In some embodiments, the risk allele at rs4676406 comprises an“A.” In some embodiments, the risk allele at rs4676399 comprises a“C.” In some embodiments, the risk allele at rs2975782 comprises an “A.” In some embodiments, the risk allele at rs3749172 comprises a“C.” In some embodiments, the risk allele at rs79844648 comprises a“G.” In some embodiments, the risk allele at rs4676402 comprises a“A” In some embodiments, the risk allele at rs2975780 comprises an“A.” In some embodiments, the risk allele at rs4676396 comprises an“A.” In some embodiments, the risk allele at rs6735672 comprises an“A.” In some embodiments, the risk allele at rs34228697 comprises an“A.” In some embodiments, the risk allele at rs4676401 compnses an“A.” In some embodiments, the risk allele at rs2975786 comprises a“G.” In some embodiments, the risk allele at rs4676346 comprises a “A.” In some embodiments, the risk allele at rs6437356 comprises a“A.” In some embodiments, the risk allele at rs6745185 comprises a“C.” In some embodiments, the risk allele at rs4676407 comprises a“G.” In some embodiments, the risk allele at rs2953156 comprises a“G.” In some embodiments, the risk allele at rs4335944 comprises a“C.” In some embodiments, the risk allele at rs73999973 comprises a“A.” In some embodiments, the risk allele at rs4676410 comprises an“A.”

In some embodiments, the risk allele at rs4676405 comprises a“G.” In some embodiments, the risk allele at rs2953154 comprises a“G.” In some embodiments, the risk allele at rs6732874 comprises an “A.” In some embodiments, the risk allele at rs55862430 comprises a“G.” In some embodiments, the risk allele at rsl2621598 comprises an“A.” In some embodiments, the risk allele at rs55919442 comprises an“A.” In some embodiments, the risk allele at rs74991608 comprises an“A.” In some embodiments, the risk allele at rs34826997 comprises a“T.” In some embodiments, the risk allele at rs6437364 comprises an“A.” The IBD may comprise Crohn’s disease, ulcerative colitis, or perianal Crohn’s disease. The increased or decreased levels of GPR35 detected in the sample may be relative to a level of GPR35 in a control subject without the IBD [00150] Disclosed herein, in some aspects, are methods of treating a subject with Crohn’s disease who is predicted to develop perianal Crohn’s disease comprising administering a therapeutically effective therapeutic agent to the subject, provided a SNP at a GPR35 locus associated with perianal Crohn’s disease is detected in a sample obtained from the subject, the SNP comprising a risk allele at rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648,

rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs467640l, rs2975786, rs4676346 , rs6437356, rs6745 l85, rs4676407, rs2953 l56, rs4335944 , rs73999973, rs46764l0 , rs4676405, rs2953154, rs6732874, rs55862430, rsl262l598, rs55919442 , rs74991608, rs34826997, rs6437364, rs20H743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62l86545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl l33726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a SNP in linkage disequilibrium therewith. In some embodiments, the SNP comprises a risk allele provided in

[brackets] within SEQ ID NO: 1-31 as shown in Table 30. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, a GPR35 genotype comprises the SNP. In some embodiments, the risk allele at rsl 13435444 comprises a“G.” In some embodiments, the risk allele at rs3749171 comprises an“A.” In some embodiments, the risk allele at rs4676406 comprises an“A.” In some embodiments, the risk allele at rs4676399 comprises a “C.” In some embodiments, the risk allele at rs2975782 comprises an“A.” In some embodiments, the risk allele at rs3749172 comprises a“C.” In some embodiments, the risk allele at rs79844648 comprises a“G.” In some embodiments, the risk allele at rs4676402 comprises a“A” In some embodiments, the risk allele at rs2975780 comprises an“A.” In some embodiments, the risk allele at rs4676396 comprises an“A.” In some embodiments, the risk allele at rs6735672 comprises an“A.”

In some embodiments, the risk allele at rs34228697 comprises an“A.” In some embodiments, the risk allele at rs4676401 comprises an“A.” In some embodiments, the risk allele at rs2975786 comprises a “G” In some embodiments, the risk allele at rs4676346 comprises a“A.” In some embodiments, the risk allele at rs6437356 comprises a“A.” In some embodiments, the risk allele at rs6745185 comprises a“C.” In some embodiments, the risk allele at rs4676407 comprises a“G” In some embodiments, the risk allele at rs2953156 comprises a“G.” In some embodiments, the risk allele at rs4335944 comprises a“C.” In some embodiments, the risk allele at rs73999973 comprises a“A.” In some embodiments, the risk allele at rs4676410 comprises an“A.” In some embodiments, the risk allele at rs4676405 comprises a“G.” In some embodiments, the risk allele at rs2953154 comprises a “G.” In some embodiments, the risk allele at rs6732874 comprises an“A.” In some embodiments, the risk allele at rs55862430 comprises a“G” In some embodiments, the risk allele at rsl2621598 comprises an“A.” In some embodiments, the risk allele at rs55919442 comprises an“A.” In some embodiments, the risk allele at rs74991608 comprises an“A.” In some embodiments, the risk allele at rs34826997 comprises a“T.” In some embodiments, the risk allele at rs6437364 comprises an“A.”

[00151] Disclosed herein, in some aspects, are methods of treating a subject with Inflammatory Bowel Disease (IBD), the method comprising administering a therapeutically effective amount of therapeutic agent targeting GPR35 signaling, provided the subject has an increased or a decreased level of GPR35 as determined by contacting a sample obtained from the subject with a probe (e.g., oligonucleotide primer or probe) targeting a SNP at a GPR35 locus associated with IBD and detecting binding between the SNP and the probe, wherein the SNP comprises a risk allele at rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl l5684595, rsl l6803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a SNP in linkage disequilibrium (LD) therewith. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, a GPR35 genotype comprises the SNP. In some embodiments, the risk allele at rsl 13435444 comprises a“G.” In some embodiments, the risk allele at rs3749171 comprises an“A.” In some embodiments, the risk allele at rs4676406 comprises an“A.” In some embodiments, the risk allele at rs4676399 comprises a“C.” In some embodiments, the risk allele at rs2975782 comprises an “A.” In some embodiments, the risk allele at rs3749172 comprises a“C.” In some embodiments, the risk allele at rs79844648 comprises a“G.” In some embodiments, the risk allele at rs4676402 comprises a“A” In some embodiments, the risk allele at rs2975780 comprises an“A.” In some embodiments, the risk allele at rs4676396 comprises an“A.” In some embodiments, the risk allele at rs6735672 comprises an“A.” In some embodiments, the risk allele at rs34228697 comprises an“A.” In some embodiments, the risk allele at rs4676401 comprises an“A.” In some embodiments, the risk allele at rs2975786 comprises a“G.” In some embodiments, the risk allele at rs4676346 comprises a “A.” In some embodiments, the risk allele at rs6437356 comprises a“A.” In some embodiments, the risk allele at rs6745185 comprises a“C.” In some embodiments, the risk allele at rs4676407 comprises a“G.” In some embodiments, the risk allele at rs2953156 comprises a“G.” In some embodiments, the risk allele at rs4335944 comprises a“C.” In some embodiments, the risk allele at rs73999973 comprises a“A.” In some embodiments, the risk allele at rs4676410 comprises an“A.”

In some embodiments, the risk allele at rs4676405 comprises a“G.” In some embodiments, the risk allele at rs2953154 comprises a“G.” In some embodiments, the risk allele at rs6732874 comprises an “A.” In some embodiments, the risk allele at rs55862430 comprises a“G.” In some embodiments, the risk allele at rsl2621598 comprises an“A.” In some embodiments, the risk allele at rs55919442 comprises an“A.” In some embodiments, the risk allele at rs74991608 comprises an“A.” In some embodiments, the risk allele at rs34826997 comprises a“T.” In some embodiments, the risk allele at rs6437364 comprises an“A.” In some embodiments, LD is determined by an r² value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0. Non-limiting examples of probes are provided in SEQ ID NOS: 32-124. In some embodiments, the SNP comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31, as shown in Table 30.

[00152] Disclosed herein, in some aspects, are methods of treating a subject with Inflammatory Bowel Disease (IBD), the method comprising administering a therapeutically effective amount of therapeutic agent targeting GPR35 signaling, provided the subject has an increased or a decreased level of GPR35 as determined by contacting a sample obtained from the subject with a probe targeting a SNP at a GPR35 locus associated with IBD and detecting binding between the SNP and the probe, wherein the SNP comprises rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rs!0933620, rs6724516, rs6708668, rsl3023028, rs!2622957, rs!2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs7699929l, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62l87776, rs62l87777, rs62l87778, rsl l33726, rsl2468485, rs62l87761, rs33986981, rs62187763, rs202l72302, rsl3428147, rs745 l2877, rs75047648, rsl2474648, or rs7857l78 l, or a SNP in linkage disequilibrium (LD) therewith. In some embodiments, LD is determined by an r² value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0. In some embodiments, the SNP comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31, as shown in Table 30. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, a GPR35 genotype comprises the SNP.

[00153] Methods of Diagnosis and Prognosis

[00154] Disclosed herein, in some embodiments, are methods of diagnosing an inflammatory disease or condition in a subject. In some cases, the inflammatory disease or condition comprises an inflammatory disease, fibrostenotic disease, and/or fibrotic disease. Non-limiting examples of inflammatory diseases include diseases of the GI tract, liver, gallbladder, and joints. In some cases, the inflammatory disease inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), or rheumatoid arthritis. In some embodiments, the disease or condition comprises fibrosis, fibrostenosis, or a fibrotic disease, either isolated or in combination with an inflammatory disease. An exemplary fibrotic disease is PSC. In some embodiments, a subtype of the disease or condition is diagnosed in the subject. Non-limiting examples of subtypes of IBD include, stricturing disease, penetrating disease, stricturing and penetrating disease, obstructive disease, refractory disease, or another complicated form of IBD. In some instances, the subject is diagnosed with, or predicted to develop, one disease or condition, two disease or conditions, three disease or conditions, or more.

[00155] Disclosed herein, in some embodiments, are methods of diagnosing a disease a disease or condition in a subject comprising: (a) obtaining a biological sample from a subject; (b) subjecting the sample to an assay configured to detect a presence, absence, or level, of a GPR35 risk genotype; (c) diagnosing the subject with the disease or condition, provided the presence, absence, or level of the GPR35 risk genotype is detected in the sample obtained from the subject. In some embodiments, the GPR35 risk genotype is detected using one or more methods of detection, kits and/or compositions disclosed herein. In some embodiments, the subject is treated by administering a therapeutically effective amount of a therapeutic agent and/or additional agent disclosed herein (e.g., activator of GPR35) to the subject, provided the subject is diagnosed with the disease or condition. In some embodiments, the GPR35 risk genotype comprises rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A, or any single nucleotide polymorphism (SNP) in linkage disequilibrium (LD) therewith. In some embodiments, the GPR35 risk genotype comprises one or more SNPs in linkage

disequilibrium with rs79844648G as determined by an r² value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0. In some embodiments, the GPR35 risk genotype comprises at least about 1 single nucleotide polymorphism (SNP), about 2 SNPs, about 3 SNPs, about 4 SNPs, about 5 SNPs, about 6 SNPs, about 7 SNPs, about 8 SNPs, about 9 SNPs, about 10 SNPs, about 11 SNPs, or more. In some embodiments, the genotype comprises one or more SNPs provided in any one of Tables 1-29. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.

[00156] Disclosed herein, in some embodiments, are methods of predicting whether a subject will develop an inflammatory disease a disease or condition, the method comprising: (a) obtaining a sample from a subject; (b) subjecting the sample to an assay configured to detect a presence, absence, or level, of a GPR35 risk genotype; (c) predicting that the subject will develop the disease or condition, provided the presence, absence, or level of the GPR35 risk genotype is detected in the sample obtained from the subject. In some embodiments, the GPR35 risk genotype is detected using one or more methods of detection, kits and/or compositions disclosed herein. In some embodiments, the subject is treated by administering a therapeutically effective amount of a therapeutic agent (e.g., activator of GPR35) and/or additional agent disclosed herein to the subject, provided the subject is predicted to develop the disease or condition. In some embodiments, the GPR35 risk genotype comprises rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A, or any single nucleotide polymorphism (SNP) in linkage disequilibrium (LD) therewith. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, the GPR35 risk genotype comprises one or more SNPs in linkage disequilibrium with rs79844648G as determined by an r² value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0. In some embodiments, the GPR35 risk genotype comprises at least about 1 single nucleotide polymorphism (SNP), about 2 SNPs, about 3 SNPs, about 4 SNPs, about 5 SNPs, about 6 SNPs, about 7 SNPs, about 8 SNPs, about 9 SNPs, about 10 SNPs, about 11 SNPs, or more. In some embodiments, the genotype comprises one or more SNPs provided in any one of Tables 1-29. In some cases, the inflammatory disease or condition comprises a fibrostenotic disease, and/or fibrotic disease Non-limiting examples of inflammatory diseases include diseases of the GI tract, liver, gallbladder, and joints. In some cases, the inflammatory disease IBD, CD, UC, systemic lupus erythematosus (SLE), or rheumatoid arthritis. In some embodiments, the disease or condition comprises fibrosis, fibrostenosis, or a fibrotic disease, either isolated or in combination with an inflammatory disease. An exemplary fibrotic disease is PSC.

[00157] Methods of Characterizing a Subtype of a Disease or Condition

[00158] Disclosed herein, in some embodiments, are methods of characterizing a disease or condition, or a subtype of a disease or condition. In some cases, the inflammatory disease or condition comprises an inflammatory disease, fibrostenotic disease, and/or fibrotic disease. Non-limiting examples of inflammatory diseases include diseases of the GI tract, liver, gallbladder, and joints. In some cases, the inflammatory disease IBD, CD, UC, systemic lupus erythematosus (SLE), or rheumatoid arthritis. In some embodiments, the disease or condition comprises fibrosis, fibrostenosis, or a fibrotic disease, either isolated or in combination with an inflammatory disease. An exemplary fibrotic disease is PSC. Non-limiting examples of subtypes of IBD include, stricturing disease, penetrating disease, stricturing and penetrating disease, obstructive disease, refractory disease, or another complicated form of IBD.

[00159] Disclosed herein, in some embodiments, are methods of characterizing a disease a disease or condition, or a subtype of a disease or condition comprising: (a) obtaining a sample from a subject;

(b) subjecting the sample to an assay configured to detect a presence, absence, or level, of GPR35 risk genotype; (c) characterizing the disease or condition as being severe, complicated, or refractory disease, provided the presence, absence, or level of GPR35 risk genotype is detected in the sample obtained from the subject. In some embodiments, the GPR35 risk genotype is detected using one or more methods of detection, kits and/or compositions disclosed herein. In some embodiments, the subject is treated by administering a therapeutically effective amount of a therapeutic agent and/or additional agent disclosed herein to the subject, provided the subject is disease or condition is characterized as severe, complicated, or refractory disease. In some embodiments, the GPR35 risk genotype comprises rs l 13435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A, or any single nucleotide polymorphism (SNP) in linkage disequilibrium (LD) therewith. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, the GPR35 risk genotype is associated with a risk that a subject has, or will develop, inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC), as determined by a P value of at most about 1.0 x 10 ⁶, about 1.0 x 10 ⁷, about 1.0 x 10 ⁸, about 1.0 x 10 ⁹, about 1.0 x 10 ¹⁰, about 1.0 x 10 ²⁰, about 1.0 x 10 ³⁰, about 1.0 x 10 ⁴⁰, about 1.0 x 10 ⁵⁰, about 1.0 x 10 ⁶⁰, about 1.0 x 10 ⁷⁰, about 1.0 x 10 ⁸⁰, about 1.0 x 10 ⁹⁰, or about 1.0 x 10 ¹⁰⁰. In some embodiments, the GPR35 risk genotype is associated with a risk that the subject has, or will develop, a subclinical phenotype or subtype of the disease or condition as determined by a P value of at most about 1.0 x 10^~6, about 1.0 x 10^~7, about 1.0 x 10 ⁸, about 1.0 x 10 ⁹, about 1.0 x 10 ¹⁰, about 1.0 x lO ²⁰, about 1.0 x 10 ³⁰, about 1.0 x 10 ⁴⁰, about 1.0 x 10^~5°, about 1.0 x 10 ⁶⁰, about 1.0 x 10 ⁷⁰, about 1.0 x 10^~80, about 1.0 x 10^~9°, or about 1.0 x 10 ¹⁰°. Non-limiting examples of subtypes and/or subclinical phenotypes of Crohn’s disease include stricturing, penetrating, stricturing and penetrating, disease phenotypes, non-response or loss of response to treatment with a standard therapy (e.g., corticosteroid, anti-TNF therapy, thiopurine therapy), perianal Crohn’s disease, and faster progression to a First Surgery or a Second Surgery. In some embodiments, the GPR35 risk genotype comprises one or more SNPs in linkage disequilibrium with rs79844648G as determined by an r² value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0. In some embodiments, the GPR35 risk genotype comprises at least about 1 single nucleotide polymorphism (SNP), about 2 SNPs, about 3 SNPs, about 4 SNPs, about 5 SNPs, about 6 SNPs, about 7 SNPs, about 8 SNPs, about 9 SNPs, about 10 SNPs, about 11 SNPs, or more. In some embodiments, the genotype comprises one or more SNPs provided in any one of Tables 1-29.

[00160] Methods of Detection

[00161] In some instances, methods comprise assaying for the presence of a SNP disclosed herein in a biological sample obtained from a subject. Disclosed herein, in some embodiments, are methods of detecting a presence, absence, or level, of a genotype or biomarker in a sample obtained from a subject. In some instances, the methods of detection disclosed herein are useful for the diagnosis, prognosis, monitoring of disease progression, selection for treatment, monitoring of treatment, and/or treatment of inflammatory bowel disease (e.g., Crohn’s disease (CD), ulcerative colitis (UC), and the like) disclosed herein.

[00162] In some instances, the subject presents a symptom of an inflammatory disease or condition described herein (e.g., IBD, CD, UC). Non-limiting example of IBD symptoms include abdominal pain, diarrhea, vomiting, weight loss, fever, anemia, skin rash, arthritis, and inflammation of the eyes. In some instances, the subject presents at least two symptoms of an IBD. In some instances, the subject presents at least three symptoms of an IBD. In some instances, methods comprise assaying for the presence of a SNP disclosed herein in a sample of a subject that has a family history (at least one family member) of IBD. In some instances, the subject has been diagnosed with the IBD. In some instances, the IBD comprises gluten intolerance. In some instances, the IBD comprises gluten sensitivity. Tests for gluten intolerance and sensitivity are known in the art (e.g., test for presence of IgA anti-gliadin antibodies). By way of non-limiting example, the IBD comprises Crohn’s disease, ulcerative colitis, microscopic colitis, diversion colitis, and Behcet's disease. In some instances, it is difficult to diagnose the IBD, and the IBD may be referred to as indeterminate colitis.

[00163] In some instances, methods disclosed herein comprise obtaining a biological sample from the subject. In some instances, the biological sample is obtained directly from the subject (e.g., at the point of care, directly from the subject). In some instances, the biological sample is obtained indirectly from the subject ( e.g at a biobank, healthcare facility, directly from the subject). The biological sample may comprise DNA. The biological sample may comprise RNA. The biological sample may comprise a cell-free nucleic acid. The biological sample may comprise a peptide. The biological sample may be a biological fluid. The biological sample may be a biological fluid that contains a nucleic acid. Non-limiting examples of biological fluids useful for the methods disclosed herein are whole blood, serum, plasma, urine, and saliva Additional biological fluids, e.g., ocular fluid, sinus fluid, lymphatic fluid, cerebrospinal fluid, could conceivably be used for methods disclosed herein. In some instances, the biological sample comprises whole cells. By way of non limiting example, the biological sample may comprise a buccal swab or skin swab. In some instances, the biological sample is non-fluidic. For example, the biological sample may comprise hair or a hair follicle.

[00164 ] Biological Samples, Sample Preparation and Gene Expression Detection

[00165] Methods, kits and systems disclosed herein are generally suitable for analyzing a biological sample obtained from a subject. Biological samples may be obtained through surgical biopsy or surgical resection. In some instances, a needle biopsy aspiration can be used to collect the a biological sample from a subject. Biological samples may be obtained by a fluid draw, swab or fluid collection. Biological samples may be obtained through primary patient derived cell lines, or archived patient samples in the form of FFPE (Formalin fixed, paraffin embedded) samples, or fresh frozen samples. Biological samples may comprise whole blood, peripheral blood, plasma, serum, saliva, cheek swab, or other bodily fluid or tissue. The sample may comprise tissue from the large and/or small intestine. The large intestine sample may comprise the cecum, colon (the ascending colon, the transverse colon, the descending colon, and the sigmoid colon), rectum and/or the anal canal. The small intestine sample may comprise the duodenum, jejunum, and/or the ileum. The sample may also comprise a blood sample. The sample may comprise serum. The sample may comprise tissue and blood.

[00166] In some embodiments, it is important to enrich and/or purify abnormal tissues and/or abnormal cells from normal tissue and/or cells of the biological sample. In some embodiments, the abnormal tissue and/or cell sample is microdissected to reduce the amount of normal tissue contamination prior to extraction of genomic nucleic acid or pre-RNA for use in the methods of the invention. Such enrichment and/or purification may be accomplished according to methods, such as needle microdissection, laser microdissection, fluorescence activated cell sorting, and immunological cell sorting.

[00167] Nucleic Acid Detection

[00168] In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification. In certain embodiments, RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene

(PreAnalytix, Switzerland).

[00169] In some embodiments, methods of detecting a presence, absence, or level of a genotype or biomarker in the sample obtained from the subject involve detecting a nucleic acid sequence. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA). In some instances, the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof. In some instances, the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single -stranded DNA (ssDNA), double-stranded DNA, denaturing double -stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some instances, the nucleic acid sequence comprises ribonucleic acid (RNA). In some instances, the nucleic acid sequence comprises fragmented RNA. In some instances, the nucleic acid sequence comprises partially degraded RNA. In some instances, the nucleic acid sequence comprises a microRNA or portion thereof. In some instances, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (IncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.

[00170] Disclosed herein, in some embodiments, the nucleic acid assayed (e.g., detected using the methods described herein) comprises at least one SNP disclosed herein. In some instances, methods comprise assaying for at least two SNPs disclosed herein. In some instances, methods comprise assaying for at least three SNPs disclosed herein. In some instances, methods comprise assaying for at least four SNPs disclosed herein. In some instances, methods comprise assaying for all SNPs disclosed herein. In some instances, methods disclose detecting the presence of at least one SNP disclosed herein. In some instances, methods comprise detecting at least two SNPs disclosed herein.

In some instances, methods comprise detecting at least three SNPs disclosed herein. Any two SNPs may be assayed for, or detected, simultaneously or sequentially. In some embodiments, the SNP assayed comprises rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs467640l, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62l86545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or any combination thereof. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, the genotype detected using the methods described herein comprises rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A. In some embodiments, the genotype detected comprises a SNP in linkage disequilibrium (LD) with one or more the above SNPs. In some embodiments, LD is determined by an r² value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0. In some embodiments, the genotype comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31 as shown in Table 30.

[00171] Disclosed herein, in some embodiments, the genotype or biomarker is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay. In some instances, the nucleic acid-based detection assay comprises quantitative polymerase chain reaction (qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunochemistry, in situ

hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, or sequencing. In some embodiments, the sequencing technique comprises next generation sequencing. In some

embodiments, the methods involve a hybridization assay such as fluorogenic qPCR (e g., TaqMan™, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence. In some instances, a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. For TaqMan™ methods, the probe may be a hydrolysable probe comprising a fluorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid. In some cases, the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles. In some instances, hybridization may occur at standard hybridization temperatures, e.g., between about 35 °C and about 65 °C in a standard PCR buffer.

[00172] An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence. In some instances, the nucleic acid probe is specific to one or more genetic variants disclosed herein is used. In some instances, the nucleic acid probe specific to a SNP or SNV comprises a nucleic acid probe sequence sufficiently complementary to a risk or protective allele of interest, such that hybridization is specific to the risk or protective allele. In some instances, the nucleic acid probe specific to an indel comprises a nucleic acid probe sequence sufficiently complementary to an insertion of a nucleobase within a polynucleotide sequence flanking the insertion, such that hybridization is specific to the indel. In some instances, the nucleic acid probe specific to an indel comprises a probe sequence sufficiently complementary to a polynucleotide sequence flanking a deletion of a nucleobase within the polynucleotide sequence, such that hybridization is specific to the indel. In some instances, the nucleic acid probe specific to a biomarker comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence of the biomarker. In some instances, the biomarker comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA). In some embodiments, the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence. In some embodiments, the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane, such as nitrocellulose. In some embodiments, the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence. Multiple alleles can be detected in individual reactions or in a single reaction (a“multiplex” assay).

[00173] The present disclosure provides exemplary probes that are hybridizable to a target nucleic acid sequence comprising a risk allele at rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, or rs6437364, and/or within a sequence selected from SEQ ID NOS: 1-124. The present disclosure provides exemplary probes provided in SEQ ID NOS: 32-124. In some embodiments, the probe comprises at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, from about 10 to about 50 nucleobases. In some embodiments, the probe comprises a sequence comprising no more than about 1, about 2, or about 3 nucleobase substitutions, insertions, or deletions from a nucleic acid selected from SEQ ID NOS: 1-124. In some embodiments, the term“probe” with regards to nucleic acids, refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some instances, probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a

chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art. In some instances, the fluorescent label comprises a fluorophore. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxaazole, mdole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin. Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N'-tetramethyl-6- carboxyrhodamine (TAMRA), 6-carboxy-X -rhodamine (ROX). Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position. For example, naphthylamino compounds include l-dimethylaminonaphthyl-5-sulfonate, l-anilino-8-naphthalene sulfonate and 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2'-aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS). Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3 -(-carboxy-pentyl)-3 '-ethyl-5,5 '-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H- Xantheno[2,3, 4-ij: 5,6, 7-i'j^,]diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-l-pyrrolidinyl)oxy]-6- oxohexyl]amino]sulfonyl]-4 (or 2)-sulfophenyl]-2,3, 6,7, 12,13, 16,17-octahydro-inner salt (TR or Texas Red); or BODIPYTM dyes. In some cases, the probe comprises FAM as the dye label. [00174] Disclosed herein, in some embodiments, a genotype or biomarker is detected by subjecting a biological sample obtained from the subject to a nucleic acid amplification assay. In some instances, the amplification assay comprises polymerase chain reaction (PCR), qPCR, self-sustained sequence replication, transcriptional amplification system, Q-Beta Replicase, rolling circle replication, or any suitable other nucleic acid amplification technique. A suitable nucleic acid amplification technique is configured to amplify a region of a nucleic acid sequence comprising one or more genetic risk variants disclosed herein. In some instances, the amplification assays requires primers. The nucleic acid sequence for the genetic risk variants and/or genes known or provided herein is sufficient to enable one of skill in the art to select primers to amplify any portion of the gene or genetic variants. A DNA sample suitable as a primer may be obtained, e.g., by polymerase chain reaction (PCR) amplification of genomic DNA, fragments of genomic DNA, fragments of genomic DNA ligated to adaptor sequences or cloned sequences. A person of skill in the art would utilize computer programs to design of primers with the desired specificity and optimal amplification properties, such as Oligo version 7.0 (National Biosciences). Controlled robotic systems are useful for isolating and amplifying nucleic acids and can be used.

[00175] Non-limiting examples of additional nucleic acid detection assays useful for the detection of a presence or absence of a genotype include restriction fragment length polymorphism (RFLP) analysis, a heteroduplex mobility assay (HMA), single strand conformational, polymorphism (SSCP), Denaturing gradient gel electrophoresis (DGGE), and RNAase mismatch techniques. As used herein, restriction fragment length polymorphism analysis is any method for distinguishing genetic polymorphisms using a restriction enzyme, which is an endonuclease that catalyzes the degradation of nucleic acid and recognizes a specific base sequence, generally a palindrome or inverted repeat. One skilled in the art understands that the use of RFLP analysis depends upon an enzyme that can differentiate two alleles at a polymorphic site. HMA is useful for detecting the presence of a polymorphic sequence since a DNA duplex carrying a mismatch has reduced mobility in a polyacrylamide gel compared to the mobility of a perfectly base-paired duplex. SSCP can be used to detect mutations based on differences in the secondary structure of single -strand DNA that produce an altered electrophoretic mobility upon non-denaturing gel electrophoresis. Polymorphic fragments are detected by comparison of the electrophoretic pattern of the test fragment to corresponding standard fragments containing known alleles. In DGGE, double-stranded DNA is electrophoresed in a gel containing an increasing concentration of denaturant; double -stranded fragments made up of mismatched alleles have segments that melt more rapidly, causing such fragments to migrate differently as compared to perfectly complementary sequences.

[00176] In some embodiments, detecting the biomarker or genotype of the subject comprises sequencing genetic material obtained from a biological sample from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g. , Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next- generation sequencing, e.g., modem sequencing technologies such as Illumina sequencing (e , Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next- generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

[00177] In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides. In some instances, the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

[00178] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs2975780. In some instances, rs2975780 is associated with increased GPR35 expression. In some instances, rs2975780 is associated with increased GPR35 activity. In some instances, rs2975780 is associated with decreased GPR35 expression. In some instances, rs2975780 is associated with decreased GPR35 activity. rs2975780 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs2975780 comprises SEQ ID NO: 9.

[00179] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676396. In some instances, rs4676396 is associated with increased GPR35 expression. In some instances, rs4676396 is associated with increased GPR35 activity. In some instances, rs4676396 is associated with decreased GPR35 expression. In some instances, rs4676396is associated with decreased GPR35 activity. rs4676396 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs4676396 comprises SEQ ID NO: 10.

[00180] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs6735672 In some instances, rs6735672 is associated with increased GPR35 expression In some instances, rs6735672 is associated with increased GPR35 activity. In some instances, rs6735672 is associated with decreased GPR35 expression. In some instances, rs6735672 is associated with decreased GPR35 activity. rs6735672 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs6735672 comprises SEQ ID NO: 11.

[00181] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs34228697. In some instances, rs34228697 is associated with increased GPR35 expression. In some instances, rs34228697 is associated with increased GPR35 activity. In some instances, rs34228697 is associated with decreased GPR35 expression. In some instances, rs34228697 is associated with decreased GPR35 activity. rs34228697 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs34228697 comprises SEQ ID NO: 12.

[00182] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676401. In some instances, rs4676401 is associated with increased GPR35 expression. In some instances, rs4676401 is associated with increased GPR35 activity. In some instances, rs4676401 is associated with decreased GPR35 expression. In some instances, rs6735672 is associated with decreased GPR35 activity. rs4676401 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs4676401 comprises SEQ ID NO: 13.

[00183] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs2975786. In some instances, rs2975786 is associated with increased GPR35 expression. In some instances, rs2975786 is associated with increased GPR35 activity. In some instances, rs2975786 is associated with decreased GPR35 expression. In some instances, rs2975786 is associated with decreased GPR35 activity. rs2975786 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs2975786 comprises SEQ ID NO: 14.

[00184] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676346. In some instances, rs4676346 is associated with increased GPR35 expression. In some instances, rs4676346 is associated with increased GPR35 activity. In some instances, rs4676346 is associated with decreased GPR35 expression. In some instances, rs4676346 is associated with decreased GPR35 activity. rs4676346 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs4676346 comprises SEQ ID NO: 15.

[00185] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs6437356. In some instances, rs6437356 is associated with increased GPR35 expression. In some instances, rs6437356 is associated with increased GPR35 activity. In some instances, rs6437356 is associated with decreased GPR35 expression. In some instances, rs6437356 is associated with decreased GPR35 activity. rs6437356 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs6437356 comprises SEQ ID NO: 16.

[00186] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs6745185. In some instances, rs6745185 is associated with increased GPR35 expression. In some instances, rs6745185 is associated with increased GPR35 activity. In some instances, rs6745185 is associated with decreased GPR35 expression. In some instances, rs6745185 is associated with decreased GPR35 activity. rs6745185 may have a risk allele of C in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs6745185 comprises SEQ ID NO: 17.

[00187] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676407. In some instances, rs4676407 is associated with increased GPR35 expression. In some instances, rs4676407 is associated with increased GPR35 activity. In some instances, rs4676407 is associated with decreased GPR35 expression. In some instances, rs4676407 is associated with decreased GPR35 activity. rs4676407 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35. A non -limiting example of a sequence including rs4676407 comprises SEQ ID NO: 18.

[00188] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs2953156. In some instances, rs2953156 is associated with increased GPR35 expression. In some instances, rs2953156 is associated with increased GPR35 activity. In some instances, rs2953156 is associated with decreased GPR35 expression. In some instances, rs2953156 is associated with decreased GPR35 activity. rs2953156 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs2953156 comprises SEQ ID NO: 19.

[00189] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4335944. In some instances, rs4335944 is associated with increased GPR35 expression. In some instances, rs4335944 is associated with increased GPR35 activity. In some instances, rs4335944 is associated with decreased GPR35 expression. In some instances, rs4335944 is associated with decreased GPR35 activity. rs4335944 may have a risk allele of C in a sense strand of a DNA molecule encoding GPR35 A non-limiting example of a sequence including rs4335944 comprises SEQ ID NO: 20 [00190] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs73999973. In some instances, rs73999973 is associated with increased GPR35 expression. In some instances, rs73999973 is associated with increased GPR35 activity. In some instances, rs73999973 is associated with decreased GPR35 expression. In some instances, rs73999973 is associated with decreased GPR35 activity. rs73999973 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs73999973 comprises SEQ ID NO: 21.

[00191] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676410. In some instances, rs4676410 is associated with increased GPR35 expression. In some instances, rs4676410 is associated with increased GPR35 activity. In some instances, rs4676410 is associated with decreased GPR35 expression. In some instances, rs4676410 is associated with decreased GPR35 activity. rs4676410 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs4676410 comprises SEQ ID NO: 22.

[00192] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676405. In some instances, rs4676405 is associated with increased GPR35 expression. In some instances, rs4676405 is associated with increased GPR35 activity. In some instances, rs4676405 is associated with decreased GPR35 expression. In some instances, rs4676405 is associated with decreased GPR35 activity. rs4676405 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs4676405 comprises SEQ ID NO: 23.

[00193] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs2953154. In some instances, rs2953154 is associated with increased GPR35 expression. In some instances, rs2953154 is associated with increased GPR35 activity. In some instances, rs2953154 is associated with decreased GPR35 expression. In some instances, rs2953154 is associated with decreased GPR35 activity. rs2953154 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs2953154 comprises SEQ ID NO: 24.

[00194] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs6732874. In some instances, rs6732874 is associated with increased GPR35 expression. In some instances, rs6732874 is associated with increased GPR35 activity. In some instances, rs6732874 is associated with decreased GPR35 expression. In some instances, rs6732874 is associated with decreased GPR35 activity. rs6732874 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs6732874 comprises SEQ ID NO: 25.

[00195] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs55862430. In some instances, rs55862430 is associated with increased GPR35 expression. In some instances, rs55862430 is associated with increased GPR35 activity. In some instances, rs55862430 is associated with decreased GPR35 expression. In some instances, rs55862430 is associated with decreased GPR35 activity. rs55862430 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs55862430 comprises SEQ ID NO: 26

[00196] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rsl2621598. In some instances, rsl2621598 is associated with increased GPR35 expression. In some instances, rsl2621598 is associated with increased GPR35 activity. In some instances, rsl2621598 is associated with decreased GPR35 expression. In some instances, rsl2621598 is associated with decreased GPR35 activity. rsl2621598 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rsl2621598 comprises SEQ ID NO: 27.

[00197] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs55919442. In some instances, rs55919442 is associated with increased GPR35 expression. In some instances, rs55919442 is associated with increased GPR35 activity. In some instances, rs55919442 is associated with decreased GPR35 expression. In some instances, rs55919442 is associated with decreased GPR35 activity. rs55919442 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs55919442 comprises SEQ ID NO: 28.

[00198] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs74991608. In some instances, rs74991608 is associated with increased GPR35 expression. In some instances, rs74991608 is associated with increased GPR35 activity. In some instances, rs74991608 is associated with decreased GPR35 expression. In some instances, rs74991608 is associated with decreased GPR35 activity. rs74991608 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs74991608 comprises SEQ ID NO: 29.

[00199] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs34826997. In some instances, rs34826997 is associated with increased GPR35 expression. In some instances, rs34826997 is associated with increased GPR35 activity. In some instances, rs34826997 is associated with decreased GPR35 expression. In some instances, rs34826997 is associated with decreased GPR35 activity. rs34826997 may have a risk allele of T in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs34826997 comprises SEQ ID NO: 30.

[00200] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs6437364. In some instances, rs6437364 is associated with increased GPR35 expression. In some instances, rs6437364 is associated with increased GPR35 activity. In some instances, rs6437364 is associated with decreased GPR35 expression. In some instances, rs6437364 is associated with decreased GPR35 activity. rs6437364 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs6437364 comprises SEQ ID NO: 31.

[00201] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rsl 13435444. In some instances, rsl 13435444 is associated with increased GPR35 expression. In some instances, rsl 13435444 is associated with increased GPR35 activity. In some instances, rsl 13435444 is associated with decreased GPR35 expression. In some instances, rsl 13435444 is associated with decreased GPR35 activity rsl 13435444 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rsl 13435444 comprises SEQ ID NO: 1.

[00202] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs3749171. In some instances, rs3749171 is associated with increased GPR35 expression. In some instances, rs3749171 is associated with increased GPR35 activity. In some instances, rs3749171 is associated with decreased GPR35 expression. In some instances, rs3749171 is associated with decreased GPR35 activity. rs3749171 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs3749171 comprises SEQ ID NO: 2.

[00203] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676406. In some instances, rs4676406 is associated with increased GPR35 expression. In some instances, rs4676406 is associated with increased GPR35 activity. In some instances, rs4676406 is associated with decreased GPR35 expression. In some instances, rs4676406 is associated with decreased GPR35 activity. rs4676406 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs4676406 comprises SEQ ID NO: 3.

[00204] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676399. In some instances, rs4676399 is associated with increased GPR35 expression. In some instances, rs4676399 is associated with increased GPR35 activity. In some instances, rs4676399 is associated with decreased GPR35 expression. In some instances, rs4676399 is associated with decreased GPR35 activity. rs4676399 may have a risk allele of C in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs4676399 comprises SEQ ID NO: 4.

[00205] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs2975782. In some instances, rs2975782 is associated with increased GPR35 expression. In some instances, rs2975782 is associated with increased GPR35 activity. In some instances, rs2975782 is associated with decreased GPR35 expression. In some instances, rs2975782 is associated with decreased GPR35 activity. rs2975782 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs2975782 comprises SEQ ID NO: 5.

[00206] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs3749172. In some instances, rs3749172 is associated with increased GPR35 expression. In some instances, rs3749172 is associated with increased GPR35 activity. In some instances, rs3749172 is associated with decreased GPR35 expression. In some instances, rs3749172 is associated with decreased GPR35 activity. rs3749172 may have a risk allele of C in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs3749172 comprises SEQ ID NO: 6

[00207] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs79844648. In some instances, rs79844648 is associated with increased GPR35 expression. In some instances, rs79844648 is associated with increased GPR35 activity. In some instances, rs79844648 is associated with decreased GPR35 expression. In some instances, rs79844648 is associated with decreased GPR35 activity. rs79844648 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs79844648 comprises SEQ ID NO: 7.

[00208] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676402. In some instances, rs4676402 is associated with increased GPR35 expression. In some instances, rs4676402 is associated with increased GPR35 activity. In some instances, rs4676402 is associated with decreased GPR35 expression. In some instances, rs4676402 is associated with decreased GPR35 activity. rs4676402 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35. A non-limiting example of a sequence including rs4676402 comprises SEQ ID NO: 8.

[00209] In some instances, methods comprise assaying for or detecting a SNP, wherein the SNP is selected from Table 1. In some instances, the SNP is associated with increased GPR35 expression. In some instances, the SNP is associated with increased GPR35 activity. In some instances, the SNP is associated with decreased GPR35 expression. In some instances, the SNP is associated with decreased GPR35 activity.

[00210] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. In some embodiments, the two SNPs comprise two SNPs selected from Table 1. In some embodiments, a SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. The two SNPs may be rsl 13435444 and rs3749171. The two SNPs may be rsl 13435444 and rs4676406. The two SNPs may be rsl 13435444 and rs4676399. The two SNPs may be rsl 13435444 and rs2975782. The two SNPs may be rsl 13435444 and rs3749172. The two SNPs may be rsl 13435444 and rs79844648. The two SNPs may be rsl 13435444 and rs4676402. The two SNPs may be rsl 13435444 and rs2975780. The two SNPs may be rsl 13435444 and rs4676396. The two SNPs may be rsl 13435444 and rs6735672. The two SNPs may be rsl 13435444 and rs34228697. The two SNPs may be rsl 13435444 and rs4676401. The two SNPs may be rsl 13435444 and rs2975786. The two SNPs may be rsl 13435444 and rs4676346. The two SNPs may be rsl 13435444 and rs6437356. The two SNPs may be rsl 13435444 and rs6745185. The two SNPs may be rsl 13435444 and rs4676407. The two SNPs may be rsl 13435444 and rs2953156. The two SNPs may be rsl 13435444 and rs4335944. The two SNPs may be rsl 13435444 and rs73999973. The two SNPs may be rsl 13435444 and rs4676410. The two SNPs may be rsl 13435444 and rs4676405. The two SNPs may be rsl 13435444 and rs2953154. The two SNPs may be rsl 13435444 and rs6732874. The two SNPs may be rsl 13435444 and rs55862430. The two SNPs may be rsl 13435444 and rsl2621598. The two SNPs may be rsl 13435444 and rs55919442. The two SNPs may be rsl 13435444 and rs74991608. The two SNPs may be rsl 13435444 and rs34826997. The two SNPs may be rsl 13435444 and rs6437364.

[00211] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs3749171and rs4676406. The two SNPs may be rs3749171 and rs4676399. The two SNPs may be rs3749171 and rs2975782. The two SNPs may be rs3749171 and rs3749172. The two SNPs may be rs3749171 and rs79844648. The two SNPs may be rs3749171 and rs4676402. The two SNPs may be rs3749171 and rs2975780. The two SNPs may be rs3749171 and rs4676396. The two SNPs may be rs3749171 and rs6735672. The two SNPs may be rs3749171 and rs34228697. The two SNPs may be rs3749171 and rs4676401. The two SNPs may be rs3749171 and rs2975786. The two SNPs may be rs3749171 and rs4676346. The two SNPs may be rs3749171 and rs6437356. The two SNPs may be rs3749171 and rs6745185. The two SNPs may be rs3749171and and rs4676407. The two SNPs may be rs3749171 and rs2953156. The two SNPs may be rs3749171 and rs4335944. The two SNPs may be rs3749171 and rs73999973. The two SNPs may be rs3749171 and rs4676410. The two SNPs may be rs3749171and and rs4676405. The two SNPs may be rs3749171 and rs2953154. The two SNPs may be rs3749171 and rs6732874. The two SNPs may be rs3749171 and rs55862430. The two SNPs may be rs3749171 and rsl2621598. The two SNPs may be rs3749171and and rs55919442. The two SNPs may be rs3749171 and rs74991608. The two SNPs may be rs3749171 and rs34826997. The two SNPs may be rs3749171 and rs6437364.

[00212] In some instances, methods comprise detecting at least two SNPs in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs4676406 and rs4676399. The two SNPs may be rs4676406 and rs2975782. The two SNPs may be rs4676406 and rs3749172 The two SNPs may be rs4676406 and rs79844648. The two SNPs may be rs4676406 and rs4676402 The two SNPs may be rs4676406 and rs2975780 The two SNPs may be rs4676406 and rs4676396. The two SNPs may be rs4676406 and rs6735672. The two SNPs may be rs4676406 and rs34228697. The two SNPs may be rs4676406 and rs4676401. The two SNPs may be rs4676406 and rs2975786. The two SNPs may be rs4676406 and rs4676346. The two SNPs may be rs4676406 and rs6437356. The two SNPs may be rs4676406 and rs6745185. The two SNPs may be rs4676406 and rs4676407 The two SNPs may be rs4676406 and rs2953156 The two SNPs may be rs4676406 and rs4335944. The two SNPs may be rs4676406 and rs73999973. The two SNPs may be rs4676406 and rs4676410. The two SNPs may be rs4676406 and rs4676405. The two SNPs may be rs4676406 and rs2953154. The two SNPs may be rs4676406 and rs6732874. The two SNPs may be rs4676406 and rs55862430. The two SNPs may be rs4676406 and rsl2621598. The two SNPs may be rs4676406 and rs55919442. The two SNPs may be rs4676406 and rs74991608. The two SNPs may be rs4676406 and rs34826997. The two SNPs may be rs4676406 and rs6437364.

[00213] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs4676399 and rs2975782. The two SNPs may be rs4676399 and rs3749172. The two SNPs may be rs4676399 and rs79844648. The two SNPs may be rs4676399 and rs4676402. The two SNPs may be rs4676399 and rs2975780. The two SNPs may be rs4676399 and rs4676396. The two SNPs may be rs4676399 and rs6735672. The two SNPs may be rs4676399 and rs34228697. The two SNPs may be rs4676399 and rs4676401. The two SNPs may be rs4676399 and rs2975786. The two SNPs may be rs4676399 and rs4676346. The two SNPs may be rs4676399 and rs6437356. The two SNPs may be rs4676399 and rs6745185. The two SNPs may be rs4676399 and rs4676407. The two SNPs may be rs4676399 and rs2953156. The two SNPs may be rs4676399 and rs4335944. The two SNPs may be rs4676399 and rs73999973. The two SNPs may be rs4676399 and rs4676410. The two SNPs may be rs4676399 and rs4676405. The two SNPs may be rs4676399 and rs2953154. The two SNPs may be rs4676399 and rs6732874. The two SNPs may be rs4676399 and rs55862430. The two SNPs may be rs4676399 and rsl2621598. The two SNPs may be rs4676399 and rs55919442. The two SNPs may be rs4676399 and rs74991608. The two SNPs may be rs4676399 and rs34826997. The two SNPs may be rs4676399 and rs6437364.

[00214] In some instances, methods comprise detecting at least two SNPs in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs2975782 and rs3749172. The two SNPs may be rs2975782 and rs79844648. The two SNPs may be rs2975782 and rs4676402. The two SNPs may be rs2975782 and rs2975780. The two SNPs may be rs2975782 and rs4676396. The two SNPs may be rs2975782 and rs6735672. The two SNPs may be rs2975782 and rs34228697. The two SNPs may be rs2975782 and rs4676401. The two SNPs may be rs2975782 and rs2975786 The two SNPs may be rs2975782 and rs4676346 The two SNPs may be rs2975782 and rs6437356. The two SNPs may be rs2975782 and rs6745185 The two SNPs may be rs2975782 and rs4676407. The two SNPs may be rs2975782 and rs2953156. The two SNPs may be rs2975782 and rs4335944. The two SNPs may be rs2975782 and rs73999973. The two SNPs may be rs2975782 and rs4676410. The two SNPs may be rs2975782 and rs4676405. The two SNPs may be rs2975782 and rs2953154. The two SNPs may be rs2975782 and rs6732874. The two SNPs may be rs2975782 and rs55862430. The two SNPs may be rs2975782 and rsl2621598. The two SNPs may be rs2975782 and rs55919442. The two SNPs may be rs2975782 and rs74991608. The two SNPs may be rs2975782 and rs34826997. The two SNPs may be rs2975782 and rs6437364.

[00215] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs3749172 and rs79844648. The two SNPs may be rs3749172 and rs4676402. The two SNPs may be rs3749172 and rs2975780. The two SNPs may be rs3749172 and rs4676396. The two SNPs may be rs3749172 and rs6735672. The two SNPs may be rs3749172 and rs34228697. The two SNPs may be rs3749172 and rs4676401. The two SNPs may be rs3749172 and rs2975786. The two SNPs may be rs3749172 and rs4676346. The two SNPs may be rs3749172 and rs6437356. The two SNPs may be rs3749172 and rs6745185. The two SNPs may be rs3749172 and rs4676407. The two SNPs may be rs3749172 and rs2953156. The two SNPs may be rs3749172 and rs4335944. The two SNPs may be rs3749172 and rs73999973. The two SNPs may be rs3749172 and rs4676410. The two SNPs may be rs3749172 and rs4676405. The two SNPs may be rs3749172 and rs2953154. The two SNPs may be rs3749172 and rs6732874. The two SNPs may be rs3749172 and rs55862430. The two SNPs may be rs3749172 and rsl2621598. The two SNPs may be rs3749172 and rs55919442. The two SNPs may be rs3749172 and rs74991608. The two SNPs may be rs3749172 and rs34826997. The two SNPs may be rs3749172 and rs6437364.

[00216] In some instances, methods comprise detecting at least two SNPs in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs79844648 and rs4676402. The two SNPs may be rs79844648 and rs2975780. The two SNPs may be rs79844648 and rs4676396. The two SNPs may be rs79844648 and rs6735672. The two SNPs may be rs79844648 and rs34228697. The two SNPs may be rs79844648 and rs4676401. The two SNPs may be rs79844648 and rs2975786. The two SNPs may be rs79844648 and rs4676346. The two SNPs may be rs79844648 and rs6437356. The two SNPs may be rs79844648 and rs6745185. The two SNPs may be rs79844648 and rs4676407. The two SNPs may be rs79844648 and rs2953156. The two SNPs may be rs79844648 and rs4335944. The two SNPs may be rs79844648 and rs73999973. The two SNPs may be rs79844648 and rs4676410. The two SNPs may be rs79844648 and rs4676405. The two SNPs may be rs79844648 and rs2953154. The two SNPs may be rs79844648 and rs6732874. The two SNPs may be rs79844648 and rs55862430. The two SNPs may be rs79844648 and rsl2621598. The two SNPs may be rs79844648 and rs55919442. The two SNPs may be rs79844648 and rs74991608. The two SNPs may be rs79844648 and rs34826997. The two SNPs may be rs79844648 and rs6437364.

[00217] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs4676402 and rs2975780. The two SNPs may be rs4676402 and rs4676396. The two SNPs may be rs4676402 and rs6735672. The two SNPs may be rs4676402 and rs34228697. The two SNPs may be rs4676402 and rs4676401. The two SNPs may be rs4676402 and rs2975786. The two SNPs may be rs4676402 and rs4676346. The two SNPs may be rs4676402 and rs6437356. The two SNPs may be rs4676402 and rs6745185. The two SNPs may be rs4676402 and rs4676407. The two SNPs may be rs4676402 and rs2953156. The two SNPs may be rs4676402 and rs4335944. The two SNPs may be rs4676402 and rs73999973. The two SNPs may be rs4676402 and rs4676410. The two SNPs may be rs4676402 and rs4676405. The two SNPs may be rs4676402 and rs2953154. The two SNPs may be rs4676402 and rs6732874. The two SNPs may be rs4676402 and rs55862430. The two SNPs may be rs4676402 and rsl2621598. The two SNPs may be rs4676402 and rs55919442. The two SNPs may be rs4676402 and rs74991608. The two SNPs may be rs4676402 and rs34826997. The two SNPs may be rs4676402 and rs6437364.

[00218] In some instances, methods comprise detecting at least two SNPs in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs2975780 and rs4676396. The two SNPs may be rs2975780 and rs6735672. The two SNPs may be rs2975780 and rs34228697. The two SNPs may be rs2975780 and rs4676401. The two SNPs may be rs2975780 and rs2975786. The two SNPs may be rs2975780 and rs4676346. The two SNPs may be rs2975780 and rs6437356. The two SNPs may be rs2975780 and rs6745185. The two SNPs may be rs2975780 and rs4676407. The two SNPs may be rs2975780 and rs2953156. The two SNPs may be rs2975780 and rs4335944. The two SNPs may be rs2975780 and rs73999973. The two SNPs may be rs2975780 and rs4676410. The two SNPs may be rs2975780 and rs4676405. The two SNPs may be rs2975780 and rs2953154. The two SNPs may be rs2975780 and rs6732874. The two SNPs may be rs2975780 and rs55862430. The two SNPs may be rs2975780 and rsl2621598. The two SNPs may be rs2975780 and rs55919442. The two SNPs may be rs2975780 and rs74991608. The two SNPs may be rs2975780 and rs34826997. The two SNPs may be rs2975780 and rs6437364. The two SNPs may be rs4676396 and rs6735672. The two SNPs may be rs4676396 and rs34228697. The two SNPs may be rs4676396 and rs4676401. The two SNPs may be rs4676396 and rs2975786. The two SNPs may be rs4676396 and rs4676346. The two SNPs may be rs4676396 and rs6437356. The two SNPs may be rs4676396 and rs6745185. The two SNPs may be rs4676396 and rs4676407. The two SNPs may be rs4676396 and rs2953156 The two SNPs may be rs4676396 and rs4335944 The two SNPs may be rs4676396 and rs73999973. The two SNPs may be rs4676396 and rs4676410. The two SNPs may be rs4676396 and rs4676405. The two SNPs may be rs4676396 and rs2953154. The two SNPs may be rs4676396 and rs6732874. The two SNPs may be rs4676396 and rs55862430. The two SNPs may be rs4676396 and rsl2621598. The two SNPs may be rs4676396 and rs55919442. The two SNPs may be rs4676396 and rs74991608. The two SNPs may be rs4676396 and rs34826997. The two SNPs may be rs4676396 and rs6437364.

[00219] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs6735672 and rs34228697. The two SNPs may be rs6735672 and rs4676401. The two SNPs may be rs6735672 and rs2975786. The two SNPs may be rs6735672 and rs4676346. The two

SNPs may be rs6735672 and rs6437356. The two SNPs may be rs6735672 and rs6745185. The two

SNPs may be rs6735672 and rs4676407. The two SNPs may be rs6735672 and rs2953156. The two

SNPs may be rs6735672 and rs4335944. The two SNPs may be rs6735672 and rs73999973. The two SNPs may be rs6735672 and rs4676410. The two SNPs may be rs6735672 and rs4676405. The two

SNPs may be rs6735672 and rs2953154. The two SNPs may be rs6735672 and rs6732874. The two

SNPs may be rs6735672 and rs55862430. The two SNPs may be rs6735672 and rsl2621598. The two SNPs may be rs6735672 and rs55919442. The two SNPs may be rs6735672 and rs74991608. The two SNPs may be rs6735672 and rs34826997. The two SNPs may be rs6735672 and rs6437364. The two SNPs may be rs34228697 and rs4676401. The two SNPs may be rs34228697 and rs2975786. The two SNPs may be rs34228697 and rs4676346. The two SNPs may be rs34228697 and rs6437356. The two SNPs may be rs34228697 and rs6745185. The two SNPs may be rs34228697 and rs4676407. The two SNPs may be rs34228697 and rs2953156. The two SNPs may be rs34228697 and rs4335944. The two SNPs may be rs34228697 and rs73999973. The two SNPs may be rs34228697 and rs4676410. The two SNPs may be rs34228697 and rs4676405. The two SNPs may be rs34228697 and rs2953154. The two SNPs may be rs34228697 and rs6732874. The two SNPs may be rs34228697 and rs55862430. The two SNPs may be rs34228697 and rs 12621598. The two SNPs may be rs34228697 and rs55919442. The two SNPs may be rs34228697 and rs74991608. The two SNPs may be rs34228697 and rs34826997. The two SNPs may be rs34228697 and rs6437364.

[00220] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs4676401 and rs2975786. The two SNPs may be rs4676401 and rs4676346. The two SNPs may be rs4676401 and rs6437356. The two SNPs may be rs4676401 and rs6745185. The two SNPs may be rs4676401 and rs4676407. The two SNPs may be rs4676401 and rs2953156. The two SNPs may be rs4676401 and rs4335944. The two SNPs may be rs4676401 and rs73999973. The two SNPs may be rs4676401 and rs4676410. The two SNPs may be rs4676401 and rs4676405. The two SNPs may be rs4676401 and rs2953154. The two SNPs may be rs4676401 and rs6732874. The two SNPs may be rs4676401 and rs55862430. The two SNPs may be rs4676401 and rsl2621598. The two SNPs may be rs4676401 and rs55919442. The two SNPs may be rs4676401 and rs74991608. The two SNPs may be rs4676401 and rs34826997. The two SNPs may be rs4676401 and rs6437364. The two SNPs may be rs2975786 and rs4676346. The two SNPs may be rs2975786 and rs6437356. The two SNPs may be rs2975786 and rs6745185. The two SNPs may be rs2975786 and rs4676407. The two SNPs may be rs2975786 and rs2953156. The two SNPs may be rs2975786 and rs4335944. The two SNPs may be rs2975786 and rs73999973. The two SNPs may be rs2975786 and rs46764l0. The two SNPs may be rs2975786 and rs4676405. The two SNPs may be rs2975786 and rs2953154. The two SNPs may be rs2975786 and rs6732874. The two SNPs may be rs2975786 and rs55862430. The two SNPs may be rs2975786 and rsl2621598. The two SNPs may be rs2975786 and rs55919442. The two SNPs may be rs2975786 and rs74991608. The two SNPs may be rs2975786 and rs34826997. The two SNPs may be rs2975786 and rs6437364.

[00221] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs4676346 and rs6437356. The two SNPs may be rs4676346 and rs6745185. The two SNPs may be rs4676346 and rs4676407. The two SNPs may be rs4676346 and rs2953156. The two SNPs may be rs4676346 and rs4335944. The two SNPs may be rs4676346 and rs73999973. The two SNPs may be rs4676346 and rs4676410. The two SNPs may be rs4676346 and rs4676405. The two SNPs may be rs4676346 and rs2953154. The two SNPs may be rs4676346 and rs6732874. The two SNPs may be rs4676346 and rs55862430. The two SNPs may be rs4676346 and rsl2621598. The two SNPs may be rs4676346 and rs55919442. The two SNPs may be rs4676346 and rs74991608. The two SNPs may be rs4676346 and rs34826997. The two SNPs may be rs4676346 and rs6437364. The two SNPs may be rs6437356 and rs6745185. The two SNPs may be rs6437356 and rs4676407. The two SNPs may be rs6437356 and rs2953156. The two SNPs may be rs6437356 and rs4335944. The two SNPs may be rs6437356 and rs73999973. The two SNPs may be rs6437356 and rs4676410. The two SNPs may be rs6437356 and rs4676405. The two SNPs may be rs6437356 and rs2953154. The two SNPs may be rs6437356 and rs6732874. The two SNPs may be rs6437356 and rs55862430. The two SNPs may be rs6437356 and rsl2621598. The two SNPs may be rs6437356 and rs55919442. The two SNPs may be rs6437356 and rs74991608. The two SNPs may be rs6437356 and rs34826997. The two SNPs may be rs6437356 and rs6437364. The two SNPs may be rs6745185 and rs4676407. The two SNPs may be rs6745185 and rs2953156. The two SNPs may be rs6745185 and rs4335944. The two SNPs may be rs6745185 and rs73999973. The two SNPs may be rs6745185 and rs4676410. The two SNPs may be rs6745185 and rs4676405. The two SNPs may be rs6745185 and rs2953154. The two SNPs may be rs6745185 and rs6732874. The two SNPs may be rs6745185 and rs55862430. The two SNPs may be rs6745185 and rsl2621598. The two SNPs may be rs6745185 and rs55919442. The two SNPs may be rs6745185 and rs74991608. The two SNPs may be rs674 185 and rs34826997. The two SNPs may be rs6745185 and rs6437364.

[00222] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs4676407 and rs2953156. The two SNPs may be rs4676407 and rs4335944. The two SNPs may be rs4676407 and rs73999973. The two SNPs may be rs4676407 and rs4676410. The two SNPs may be rs4676407 and rs4676405. The two SNPs may be rs4676407 and rs2953154. The two SNPs may be rs4676407 and rs6732874. The two SNPs may be rs4676407 and rs55862430. The two SNPs may be rs4676407 and rsl2621598. The two SNPs may be rs4676407 and rs55919442. The two SNPs may be rs4676407 and rs74991608. The two SNPs may be rs4676407 and rs34826997. The two SNPs may be rs4676407 and rs6437364. The two SNPs may be rs2953156 and rs4335944. The two SNPs may be rs2953156 and rs73999973. The two SNPs may be rs2953156 and rs4676410. The two SNPs may be rs2953156 and rs4676405. The two SNPs may be rs2953156 and rs2953154. The two SNPs may be rs2953156 and rs6732874. The two SNPs may be rs2953156 and rs55862430. The two SNPs may be rs2953156 and rsl2621598. The two SNPs may be rs2953156 and rs55919442. The two SNPs may be rs2953156 and rs74991608. The two SNPs may be rs2953156 and rs34826997. The two SNPs may be rs2953156 and rs6437364. The two SNPs may be rs4335944 and rs73999973. The two SNPs may be rs4335944 and rs4676410. The two SNPs may be rs4335944 and rs4676405. The two SNPs may be rs4335944 and rs2953154. The two SNPs may be rs4335944 and rs6732874. The two SNPs may be rs4335944 and rs55862430. The two SNPs may be rs4335944 and rsl2621598. The two SNPs may be rs4335944 and rs55919442. The two SNPs may be rs4335944 and rs74991608. The two SNPs may be rs4335944 and rs34826997. The two SNPs may be rs4335944 and rs6437364.

[00223] In some instances, methods comprise detecting at least two SNPs in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs73999973 and rs4676410. The two SNPs may be rs73999973 and rs4676405. The two SNPs may be rs73999973 and rs2953154. The two SNPs may be rs73999973 and rs6732874. The two SNPs may be rs73999973 and rs55862430. The two SNPs may be rs73999973 and rsl2621598. The two SNPs may be rs73999973 and rs55919442. The two SNPs may be rs73999973 and rs74991608. The two SNPs may be rs73999973 and rs34826997. The two SNPs may be rs73999973 and rs6437364. The two SNPs may be rs4676410 and rs4676405. The two SNPs may be rs4676410 and rs2953154. The two SNPs may be rs4676410 and rs6732874. The two SNPs may be rs4676410 and rs55862430. The two SNPs may be rs4676410 and rsl2621598. The two SNPs may be rs4676410 and rs55919442. The two SNPs may be rs4676410 and rs74991608. The two SNPs may be rs4676410 and rs34826997. The two SNPs may be rs4676410 and rs6437364. The two SNPs may be rs4676405 and rs2953154 The two SNPs may be rs4676405 and rs6732874. The two SNPs may be rs4676405 and rs55862430. The two SNPs may be rs4676405 and rsl2621598. The two SNPs may be rs4676405 and rs55919442. The two SNPs may be rs4676405 and rs74991608. The two SNPs may be rs4676405 and rs34826997. The two SNPs may be rs4676405 and rs6437364.

[00224] In some instances, methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35. The two SNPs may be rs2953154 and rs6732874. The two SNPs may be rs2953154 and rs55862430. The two SNPs may be rs2953154 and rsl2621598. The two SNPs may be rs2953154 and rs55919442. The two

SNPs may be rs2953154 and rs74991608. The two SNPs may be rs2953154 and rs34826997. The two

SNPs may be rs2953154 and rs6437364. The two SNPs may be rs6732874 and rs55862430. The two SNPs may be rs6732874 and rsl2621598. The two SNPs may be rs6732874 and rs55919442. The two

SNPs may be rs6732874 and rs74991608. The two SNPs may be rs6732874 and rs34826997. The two

SNPs may be rs6732874and rs6437364. The two SNPs may be rs55862430 and rsl2621598. The two SNPs may be rs55862430 and rs55919442. The two SNPs may be rs55862430 and rs74991608. The two SNPs may be rs55862430 and rs34826997. The two SNPs may be rs55862430 and rs6437364. The two SNPs may be rsl2621598 and rs55919442. The two SNPs may be rsl2621598 and rs74991608. The two SNPs may be rsl2621598 and rs34826997. The two SNPs may be rsl2621598 and rs6437364. The two SNPs may be rs55919442 and rs74991608. The two SNPs may be rs55919442 and rs34826997. The two SNPs may be rs55919442 and rs6437364. The two SNPs may be rs74991608 and rs34826997. The two SNPs may be rs74991608 and rs6437364. The two SNPs may be rs34826997 and rs6437364.

[00225] Protein/Polypeptide Detection

[00226] In some embodiments, methods of detecting a presence, absence, or level of a target protein (e.g., biomarker) in the sample obtained from the subject involve detecting protein activity or expression. A target protein may be detected by use of an antibody-based assay, where an antibody specific to the target protein is utilized. In some embodiments, antibody-based detection methods utilize an antibody that binds to any region of target protein. An exemplary method of analysis comprises performing an enzyme-linked immunosorbent assay (ELISA). The ELISA assay may be a sandwich ELISA or a direct ELISA. Another exemplary method of analysis comprises a single molecule array, e.g., Simoa. Other exemplary methods of detection include immunohistochemistry and lateral flow assay. Additional exemplary methods for detecting target protein include, but are not limited to, gel electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, and the like, or various immunological methods such as fluid or gel precipitation reactions, immunodiffusion (single or double), Immunoelectrophoresis, radioimmunoassay (RIA), immunofluorescent assays, and Western blotting. In some embodiments, antibodies, or antibody fragments, are used in methods such as Western blots or immunofluorescence techniques to detect the expressed proteins The antibody or protein can be immobilized on a solid support for Western blots and immunofluorescence techniques. Suitable solid phase supports or carriers include any support capable of binding an antigen or an antibody. Exemplary supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.

[00227] In some cases, a target protein may be detected by detecting binding between the target protein and a binding partner of the target protein. In some cases, the target protein comprises GPR35, or another protein involved in the GPR35. Exemplary methods of analysis of protein-protein binding comprise performing an assay in vivo or in vitro, or ex vivo. In some instances, the method of analysis comprises an assay such as a co-immunoprecipitation (co-IP), pull-down, crosslinking protein interaction analysis, labeled transfer protein interaction analysis, or Far-western blot analysis, FRET based assay, including, for example FRET-FLIM, a yeast two-hybrid assay, BiFC, or split luciferase assay.

[00228] Disclosed herein, in some embodiments, are methods of detecting a presence or a level of one or more serological markers in a sample obtained from a subject. In some embodiments, the serological marker may be a nucleic acid. The nucleic acid may comprise DNA. The nucleic acid may comprise RNA. The nucleic acid may be a cell-free nucleic acid. The marker may be a protein. The protein may also be referred to herein as a“peptide.” The protein may be a human protein. The protein may be a non-human protein. The protein may be an antibody or antibody fragment. In some embodiments, the antibodies comprises immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin E (IgE), or immunoglobulin M (IgM), immunoglobulin D (IgD), or a combination thereof. The antibody or antibody fragment may bind an antigen, wherein the antigen is a bacterial particle. The antibody or antibody fragment may bind an antigen, wherein the antigen is a yeast particle. The antibody or antibody fragment may bind an antigen, wherein the antigen is a viral particle. The term,“particle,” may refer to a nucleic acid, peptide or other cellular component. The antibody or antibody fragment may bind an antigen on a cell of the subject. By way of non -limiting example, the protein may be an ssAi-Saccharomyces cerevisiae antibody (ASCA), an anti-neutrophil cytoplasmic antibody (ANCA), or an E.coli outer membrane porin protein C (OmpC). Any suitable method for detecting a target protein or biomarker disclosed herein may be used to detect a presence, absence, or level of a serological marker.

[00229] Disclosed herein, in some embodiments, the presence or the level of the one or more serological markers is detected using an enzyme-linked immunosorbent assay (ELISA), a single molecule array (Simoa), immunohistochemistry, internal transcribed spacer (ITS) sequencing, or any combination thereof. In some embodiments, the ELISA is a fixed leukocyte ELISA. In some embodiments, the ELISA is a fixed neutrophil ELISA. A fixed leukocyte or neutrophil ELISA may be useful for the detection of certain serological markers, such as those described in Saxon et al ., A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease, J Allergy Clin. Immuno. 86:2; 202-210 (August 1990). In some embodiments, ELISA units (EU) are used to measure positivity of a presence or level of a serological marker (e.g.,

seropositivity), which reflects a percentage of a standard or reference value. In some embodiments, the standard comprises pooled sera obtained from well-characterized patient population (e g., diagnosed with the same disease or condition the subject has, or is suspected of having) reported as being seropositive for the serological marker of interest. In some embodiments, the control or reference value comprises 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 EU. In some instances, a quartile sum scores are calculated using, for example, the methods reported in Landers C J, Cohavy O, Misra R. et al, Selected loss of tolerance evidenced by Crohn's disease-associated immune responses to auto- and microbial antigens. Gastroenterology (2002)123:689-699.

[00230] In some instances, methods comprise quantifying a protein in a biological sample of the subject. Non-limiting examples of methods for protein quantification include immunohistochemistry and immunocytochemistry with detectable markers (e.g., dyes, fluorescence, luminescence). A gold standard for protein quantification is an enzyme-linked immunosorbent assay (ELISA). In some instances, the ELISA is fixed. In some instances, the fixed ELISA comprises fixed granulocytes. In some instances, methods comprise quantifying the protein to obtain a protein quantity and comparing the protein quantity to a reference protein quantity. In some instances, the reference protein quantity if a protein quantity in a corresponding biological sample from a reference subject. The reference subject may have an IBD. The reference subject may have the same IBD as the subject. The reference subject may have the same IBD that the subject is suspected of having. The reference subject may not have an IBD. The reference subject may not have the same IBD as the subject. The reference subject may not have the same IBD that the subject is suspected of having. The reference subject may be a healthy subject (not diagnosed with any disease or condition). The reference subject may be diagnosed with any inflammatory condition.

[00231] In some instances, methods comprise quantifying a marker (e.g., biomarker, serological marker) quantity and a reference marker quantity and detecting a difference between the marker quantity and the reference quantity. In some instances, methods comprise detecting a marker quantity and detecting multiple reference marker quantities and detecting that the marker quantity falls within a range of reference marker quantities. In some instances, methods comprise detecting a marker quantity and detecting multiple reference marker quantities and detecting that the marker quantity falls outside a range of reference marker quantities. Methods may comprise detecting a statistically significant difference between a marker quantity and one or more reference quantities. Statistical significance may be determined by a variety of methods.

KITS AND COMPOSITIONS

[00232] Compositions

[00233] Disclosed herein, in some embodiments, are compositions useful for the detection of a genotype or biomarker in a sample obtained from a subject according to the methods described herein. Aspects disclosed herein provide compositions comprises a polynucleotide sequence comprising at least 10 but less than 50 contiguous nucleotides of any one of SEQ ID NOS: 32-124, or reverse complements thereof, wherein the contiguous polynucleotide sequence comprises a detectable molecule. In some embodiments, the contiguous nucleotides are suitable to detect a genotype comprising rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, rs6437364A, and/or a sequence selected from SEQ ID NOS: 32-124. In various embodiments, the detectable molecule comprises a fluorophore. In other embodiments, the polynucleotide sequences further comprise a quencher.

[00234] Also disclosed herein are compositions comprising an antibody or antigen-binding fragment that specifically binds to GPR35, or a portion thereof, wherein the antibody or antigen-binding fragment comprises a detectable molecule. In various embodiments, the antibody comprises a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a Fab, a Fab’, a F(ab’)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, or a bispecific antibody. In some embodiments, the antibody or antigen-binding fragment comprises an IgG antibody, an IgM antibody, and/or an IgE antibody. In some embodiments, the detectable molecule comprises a fluorophore. In some embodiments, the antibody or antigen-binding fragment is conjugated to a paramagnetic particle (e g., bead).

[00235] Disclosed herein, in some embodiments, are kits useful for detecting the genotypes and/or biomarkers disclosed herein. In some embodiments, the kits disclosed herein may be used to diagnose and/or treat a disease or condition in a sub_ject; or select a patient for treatment and/or monitor a treatment disclosed herein. In some embodiments, the kit comprises the compositions described herein, which can be used to perform the methods described herein. Kits comprise an assemblage of materials or components, including at least one of the compositions. Thus, in some embodiments the kit contains a composition including of the pharmaceutical composition, for the treatment of IBD. In other embodiments, the kits contains all of the components necessary and/or sufficient to perform an assay for detecting and measuring IBD markers, including all controls, directions for performing assays, and any necessary software for analysis and presentation of results.

[00236] In some instances, the kits described herein comprise components for detecting the presence, absence, and/or quantity of a target nucleic acid and/or protein described herein. In some

embodiments, the kit further comprises components for detecting the presence, absence, and/or quantity of a serological marker described herein. In some embodiments, the kit comprises the compositions (e g., primers, probes, antibodies) described herein. The disclosure provides kits suitable for assays such as enzyme-linked immunosorbent assay (ELISA), single -molecular array (Simoa), PCR, and qPCR. The exact nature of the components configured in the kit depends on its intended purpose. For example, some embodiments are configured for the purpose of treating a disease or condition disclosed herein (e.g., IBD, CD, UC) in a subject. In some embodiments, the kit is configured particularly for the purpose of treating mammalian subjects. In some embodiments, the kit is configured particularly for the purpose of treating human subjects. In further embodiments, the kit is configured for veterinary applications, treating subjects such as, but not limited to, farm animals, domestic animals, and laboratory animals. In some embodiments, the kit is configured to select a subject for a therapeutic agent, such as those disclosed herein. In some embodiments, the kit is configured to select a subject for treatment with an activator of GPR35 activity or expression.

[00237] Kits

[00238] Disclosed herein, in some aspects are kits that comprise a set of oligonucleotides for detecting a combination of single nucleotide polymorphisms selected from rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402, rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364 rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl l3444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl l5684595, rsl l6803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, and rs78571781. In some embodiments, a SNP is positioned within a sequence selected from SEQ ID NOS: 1-124.

[00239] Disclosed herein, in some embodiments, are kits comprising a set of oligonucleotides for detecting a genotype comprising rsl 13435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, rs6437364A, a sequence selected from SEQ ID NOS: 1-124, or any combination thereof. In some embodiments, the genotype is heterozygous, or homozygous Kits may be used according to methods disclosed herein. [00240] In some instances, kits disclosed herein comprise a microarray chip, wherein the microarray comprises oligonucleotide probes on the microarray chip. Non-limiting examples of probes are provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 90% identical to a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 95% identical to a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 97% identical to a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 98% identical to a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 90% identical to a complement of a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 95% identical to a complement of a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 97% identical to a complement of a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 98% identical to a complement of a probe provided in SEQ ID NOS: 32- 124.

[00241] In some instances, kits disclosed herein comprise an oligonucleotide primer that is capable of amplifying a portion of a GPR35 gene locus. In some instances, kits disclosed herein comprise an oligonucleotide primer pair that is capable of amplifying a portion of a GPR35 gene locus. In some instances, kits disclosed herein further comprise a probe that is useful for performing Q-PCR with the oligonucleotide primer(s). An oligonucleotide primer may be complementary to a portion of an exon of the GPR35 gene locus. An oligonucleotide primer may be complementary to a portion of an intron of the GPR35 gene locus.

[00242] In some instances, kits disclosed herein comprise a probe for a protein. In some instances, the probe is an antibody or antigen binding antibody fragment. In some instances, the probe is an antigen. In some instances, the probe is a peptide comprising an antigen epitope. In some instances, the probe comprises a small molecule or peptide that can bind the protein. In some instances, the probe is labeled with a detectable signal. In some instances, the probe comprises a detectable signal. In some instances, the protein is an enzyme and the probe is a substrate. Methods may comprise detecting components of the substrate after it has been processed by the enzyme. The protein may be a serological marker. In some instances, the serological marker is an anti -Saccharomyces cerevisiae antibody (ASCA). In some instances, the serological marker is an anti -neutrophil cytoplasmic antibody (ANCA). In some instances, the serological marker is an E.coli outer membrane porin protein C (OmpC). The kit may comprise an enzyme-linked immunosorbent assay (ELISA), or immunohistochemistry reagent. For ANCA, the ELISA may comprise fixed neutrophils as described in Saxon et ak, J Allergy Clin Immunol 1990 86:202-210, incorporated herein by reference.

[00243] Kits and methods comprise oligonucleotides or uses thereof. In some instances, the oligonucleotide is a probe. In some instances, the probe comprises a sequence in SEQ ID NOS: 32- 124, or a complement thereof. In some instances, the probe comprises a sequence, or a complement thereof, that is at least about 85% identical to a sequence in SEQ ID NOS: 32-124. In some instances, the probe comprises a sequence, or a complement thereof, that is at least about 90% identical to a sequence in SEQ ID NOS: 32-124. In some instances, the probe comprises a sequence, or a complement thereof, that is at least about 95% identical to a sequence in SEQ ID NOS: 32-124. In some instances, the probe comprises a sequence, or a complement thereof, that is identical to at least about 10 nucleotides, at least about 15 nucleotides, at least about 20 nucleotides, at least about 25 nucleotides, at least about 30 nucleotides, at least about 35 nucleotides, at least about 40 nucleotides, or at least about 45 nucleotides of a sequence provided in SEQ ID NOS: 32-124.

[00244] In some instances, the oligonucleotide is a primer. In some instances the primer is capable of amplifying a region surrounding the polymorphism. In some instances, the oligonucleotide is capable of binding to a region of a nucleic acid surrounding the polymorphism. In some instances, the region surrounding the polymorphism is a sequence provided in SEQ ID NOS: 32-124, or a complement thereof. In some instances, the region surrounding the polymorphism is at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 98% identical to a sequence provided in SEQ ID NOS: 32-124, or a complement thereof. In some instances, the region surrounding the polymorphism comprises at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90 or at least about 100 consecutive nucleotides of a sequence provided in SEQ ID NOS: 32-124, or a complement thereof.

[00245] Instructions for use may be included in the kit. Optionally, the kit also contains other useful components, such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia. The materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility. For example the components can be in dissolved, dehydrated, or lyophilized form; they can be provided at room, refrigerated or frozen temperatures. The components are typically contained in suitable packaging material (s). As employed herein, the phrase“packaging material” refers to one or more physical structures used to house the contents of the kit, such as compositions and the like. The packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment. The packaging materials employed in the kit are those customarily utilized in gene expression assays and in the administration of treatments. As used herein, the term“package” refers to a suitable solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding the individual kit components. Thus, for example, a package can be a glass vial or prefilled syringes used to contain suitable quantities of the pharmaceutical composition. The packaging material has an external label which indicates the contents and/or purpose of the kit and its components.

SYSTEMS

[00246] Disclosed herein, in some embodiments, are systems for detecting a genotype (e.g., one or more SNPs) disclosed herein. Also disclosed herein, in some embodiments, are systems for detecting a subject’s response to a therapeutic agent disclosed herein. The response may be a change in gene expression in a cell of the subject. Accordingly, in some instances, systems may be configured to analyze gene expression in a biological sample obtained from a subject. The response may be a change in protein quantity or protein activity. Systems may be configured to quantify an RNA. Systems may be configured to quantify a protein. Systems may be configured to assess a protein’s activity. The protein may be GPR35. The protein may be a protein that interacts with GPR35. The protein may be a protein that functions downstream of GPR35. The protein may be a protein that functions upstream of GPR35. The system is configured to implement the methods described in this disclosure, including, but not limited to, analyzing genes or gene expression products from the genes of a subject to determine whether the subject is, or is susceptible to being, non -responsive to a therapeutic agent disclosed herein.

[00247] In some embodiments, disclosed herein is a system for detecting a SNP disclosed herein in a biological sample from a subject, comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze a gene or gene expression product from GPR35 in a biological sample from a subject. In some embodiments, disclosed herein is a system for detecting a subject’s response to a therapeutic agent disclosed herein, comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze a gene or gene expression product from GPR35 in a biological sample from a subject. In some embodiments, disclosed herein is a system for detecting a subject’s response to a therapeutic agent disclosed herein, comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze GPR35 activity in a biological sample from a subject. In some embodiments, disclosed herein is a system for detecting a subject’s response to a therapeutic agent disclosed herein, comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze GPR35 interactions with other proteins in a biological sample from a subject. In some embodiments, disclosed herein is a system for detecting a subject’s response to a therapeutic agent disclosed herein, comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze proteins that function downstream of GPR35 in a biological sample from a subject. Proteins that function downstream of GPR35 may include components of intracellular signaling pathways. By way of non-limiting example, G protein-coupled receptors often trigger intracellular signaling pathways involving Rho GTPases, phospholipases, ERK proteins, protein kinases, and AKT. Such signaling may also result in intracellular amounts of cAMP, ATP, calcium, etc.

[00248] In some instances, systems comprise a central processing unit (CPU), memory (e g., random access memory, flash memory), electronic storage unit, computer program, communication interface to communicate with one or more other systems, and any combination thereof. In some instances, systems are coupled to a computer network, for example, the Internet, intranet, and/or extranet that is in communication with the Internet, a telecommunication, or data network. In some embodiments, systems comprise a storage unit to store data and information regarding any aspect of the methods described in this disclosure. Various aspects of systems are a product or article or manufacture.

[00249] One feature of a computer program includes a sequence of instructions, executable in the digital processing device’s CPU, written to perform a specified task. In some embodiments, ccomputer readable instructions are implemented as program modules, such as functions, features, Application Programming Interfaces (APIs), data structures, and the like, that perform particular tasks or implement particular abstract data types. In light of the disclosure provided herein, those of skill in the art will recognize that a computer program may be written in various versions of various languages.

[00250] The functionality of the computer readable instructions are combined or distributed as desired in various environments. In some instances, a computer program comprises one sequence of instructions or a plurality of sequences of instructions. A computer program may be provided from one location. A computer program may be provided from a plurality of locations. In some embodiment, a computer program includes one or more software modules. In some embodiments, a computer program includes, in part or in whole, one or more web applications, one or more mobile applications, one or more standalone applications, one or more web browser plug-ins, extensions, add ins, or add-ons, or combinations thereof.

[00251] Web application

[00252] In some embodiments, a computer program includes a web application. In light of the disclosure provided herein, those of skill in the art will recognize that a web application may utilize one or more software frameworks and one or more database systems. A web application, for example, is created upon a software framework such as Microsoft® .NET or Ruby on Rails (RoR). A web application, in some instances, utilizes one or more database systems including, by way of non limiting examples, relational, non-relational, feature oriented, associative, and XML database systems. Suitable relational database systems include, by way of non-limiting examples, Microsoft® SQL Server, mySQL™, and Oracle®. Those of skill in the art will also recognize that a web application may be written in one or more versions of one or more languages. In some embodiments, a web application is written in one or more markup languages, presentation definition languages, client-side scripting languages, server-side coding languages, database query languages, or combinations thereof. In some embodiments, a web application is written to some extent in a markup language such as Hypertext Markup Language (HTML), Extensible Hypertext Markup Language (XHTML), or extensible Markup Language (XML). In some embodiments, a web application is written to some extent in a presentation definition language such as Cascading Style Sheets (CSS). In some embodiments, a web application is written to some extent in a client-side scripting language such as Asynchronous Javascript and XML (AJAX), flash® Actionscript, Javascript, or Silverlight®. In some embodiments, a web application is written to some extent in a server-side coding language such as Active Server Pages (ASP), ColdFusion®, Perl, Java™, JavaServer Pages (JSP), Hypertext Preprocessor (PHP), Python™, Ruby, Tel, Smalltalk, WebDNA®, or Groovy. In some embodiments, a web application is written to some extent in a database query language such as Structured Query Language (SQL). A web application may integrate enterprise server products such as IBM® Lotus Domino®. A web application may include a media player element. A media player element may utilize one or more of many suitable multimedia technologies including, by way of non-limiting examples, Adobe® Flash®, HTML 5, Apple® QuickTime®, Microsoft® Silverlight®, Java™, and Unity®.

[00253] Mobile application

[00254] In some instances, a computer program includes a mobile application provided to a mobile digital processing device. The mobile application may be provided to a mobile digital processing device at the time it is manufactured. The mobile application may be provided to a mobile digital processing device via the computer network described herein.

[00255] A mobile application is created by techniques known to those of skill in the art using hardware, languages, and development environments known to the art. Those of skill in the art will recognize that mobile applications may be written in several languages. Suitable programming languages include, by way of non-limiting examples, C, C++, C#, Featureive-C, Java™, Javascript, Pascal, Feature Pascal, Python™, Ruby, VB.NET, WML, and XHTML/HTML with or without CSS, or combinations thereof.

[00256] Suitable mobile application development environments are available from several sources. Commercially available development environments include, by way of non-limiting examples, AirplaySDK, alcheMo, Appcelerator®, Celsius, Bedrock, Flash Lite, .NET Compact Framework, Rhomobile, and WorkLight Mobile Platform. Other development environments may be available without cost including, by way of non-limiting examples, Lazarus, MobiFlex, MoSync, and

Phonegap. Also, mobile device manufacturers distribute software developer kits including, by way of non-limiting examples, iPhone and iPad (iOS) SDK, Android™ SDK, BlackBerry® SDK, BREW SDK, Palm® OS SDK, Symbian SDK, webOS SDK, and Windows® Mobile SDK.

[00257] Those of skill in the art will recognize that several commercial forums are available for distribution of mobile applications including, by way of non-limiting examples, Apple® App Store, Android™ Market, BlackBerry® App World, App Store for Palm devices, App Catalog for webOS, Windows® Marketplace for Mobile, Ovi Store for Nokia® devices, Samsung® Apps, and Nintendo® DSi Shop.

[00258] Standalone application

[00259] In some embodiments, a computer program includes a standalone application, which is a program that may be run as an independent computer process, not an add-on to an existing process, e g ., not a plug-in. Those of skill in the art will recognize that standalone applications are sometimes compiled. In some instances, a compiler is a computer program(s) that transforms source code written in a programming language into binary feature code such as assembly language or machine code. Suitable compiled programming languages include, by way of non-limiting examples, C, C++, Featureive-C, COBOL, Delphi, Eiffel, Java™, Lisp, Python™, Visual Basic, and VB .NET, or combinations thereof. Compilation may be often performed, at least in part, to create an executable program. In some instances, a computer program includes one or more executable complied applications.

[00260] Web browser plug-in

[00261] A computer program, in some aspects, includes a web browser plug-in. In computing, a plug in, in some instances, is one or more software components that add specific functionality to a larger software application. Makers of software applications may support plug-ins to enable third-party developers to create abilities which extend an application, to support easily adding new features, and to reduce the size of an application. When supported, plug-ins enable customizing the functionality of a software application. For example, plug-ins are commonly used in web browsers to play video, generate interactivity, scan for viruses, and display particular file types. Those of skill in the art will be familiar with several web browser plug-ins including, Adobe® Flash® Player, Microsoft® Silverlight®, and Apple® QuickTime®. The toolbar may comprise one or more web browser extensions, add-ins, or add-ons. The toolbar may comprise one or more explorer bars, tool bands, or desk bands.

[00262] In view of the disclosure provided herein, those of skill in the art will recognize that several plug-in frameworks are available that enable development of plug-ins in various programming languages, including, by way of non-limiting examples, C++, Delphi, Java™, PHP, Python™, and VB .NET, or combinations thereof.

[00263] In some embodiments, Web browsers (also called Internet browsers) are software applications, designed for use with network-connected digital processing devices, for retrieving, presenting, and traversing information resources on the World Wide Web. Suitable web browsers include, by way of non-limiting examples, Microsoft® Internet Explorer®, Mozilla® Firefox®, Google® Chrome, Apple® Safari®, Opera Software® Opera®, and KDE Konqueror. The web browser, in some instances, is a mobile web browser. Mobile web browsers (also called

mircrobrowsers, mini-browsers, and wireless browsers) may be designed for use on mobile digital processing devices including, by way of non-limiting examples, handheld computers, tablet computers, netbook computers, subnotebook computers, smartphones, music players, personal digital assistants (PDAs), and handheld video game systems. Suitable mobile web browsers include, by way of non-limiting examples, Google® Android® browser, RIM BlackBerry® Browser, Apple®

Safari®, Palm® Blazer, Palm® WebOS® Browser, Mozilla® Firefox® for mobile, Microsoft® Internet Explorer® Mobile, Amazon® Kindle® Basic Web, Nokia® Browser, Opera Software® Opera® Mobile, and Sony® PSP™ browser. [00264] Software modules

[00265] The medium, method, and system disclosed herein comprise one or more softwares, servers, and database modules, or use of the same. In view of the disclosure provided herein, software modules may be created by techniques known to those of skill in the art using machines, software, and languages known to the art. The software modules disclosed herein may be implemented in a multitude of ways. In some embodiments, a software module comprises a file, a section of code, a programming feature, a programming structure, or combinations thereof. A software module may comprise a plurality of files, a plurality of sections of code, a plurality of programming features, a plurality of programming structures, or combinations thereof. By way of non-limiting examples, the one or more software modules comprises a web application, a mobile application, and/or a standalone application. Software modules may be in one computer program or application. Software modules may be in more than one computer program or application. Software modules may be hosted on one machine. Software modules may be hosted on more than one machine. Software modules may be hosted on cloud computing platforms. Software modules may be hosted on one or more machines in one location. Software modules may be hosted on one or more machines in more than one location.

[00266] Databases

[00267] The medium, method, and system disclosed herein comprise one or more databases, or use of the same. In view of the disclosure provided herein, those of skill in the art will recognize that many databases are suitable for storage and retrieval of geologic profile, operator activities, division of interest, and/or contact information of royalty owners. Suitable databases include, by way of non limiting examples, relational databases, non-relational databases, feature oriented databases, feature databases, entity-relationship model databases, associative databases, and XML databases. In some embodiments, a database is internet-based. In some embodiments, a database is web-based. In some embodiments, a database is cloud computing-based. A database may be based on one or more local computer storage devices.

[00268] Data transmission

[00269] The subject matter described herein, including methods for obtaining and analyzing a molecular signature from a subject having a pigmented skin lesion, methods for obtaining a pigmented skin lesion, corresponding transmission of data, in certain aspects, are configured to be performed in one or more facilities at one or more locations. Facility locations are not limited by country and include any country or territory. In some instances, one or more steps for obtaining a molecular signature from a sample are performed in a different country than another step of the method. In some instances, one or more steps for obtaining a sample are performed in a different country than one or more steps for obtaining a molecular signature from a sample. In some embodiments, one or more method steps involving a computer system are performed in a different country than another step of the methods provided herein. In some embodiments, data processing and analyses are performed in a different country or location than one or more steps of the methods described herein. In some embodiments, one or more articles, products, or data are transferred from one or more of the facilities to one or more different facilities for analysis or further analysis. An article includes, but is not limited to, one or more components obtained from the genotyping assay, processed cellular material, data, and any article or product disclosed herein as an article or product. Processed cellular material includes, but is not limited to, cDNA reverse transcribed from RNA. amplified RNA, amplified cDNA, sequenced DNA, isolated and/or purified RNA, isolated and/or purified DNA, and isolated and/or purified polypeptide. Data includes, but is not limited to, information regarding the gene expression profile of one or more target genes, information regarding a gene sequence profile signature, information regarding a protein sequence profile, information regarding the characteristic of a pigmented skin lesion (e.g., non-melanoma, melanoma in situ, invasive melanoma, stage 1 melanoma, stage 2 melanoma, stage 3 melanoma, stage 4 melanoma), and any data produced by the methods disclosed herein. In some embodiments of the methods and systems described herein, the analysis is performed and a subsequent data transmission step will convey or transmit the results of the analysis. Information regarding a pigmented skin lesion includes, but is not limited to, identification of melanoma, likelihood of treatment success for a subject having melanoma, identification of progression of a melanoma, identification of melanoma in situ, identification of invasive melanoma, and identification of a melanoma stage (e.g., 0, 1, 2, 3, 4).

[00270] In some embodiments, any step of any method described herein is performed by a software program or module on a computer. In additional or further embodiments, data from any step of any method described herein is transferred to and from facilities located within the same or different countries, including analysis performed in one facility in a particular location and the data shipped to another location or directly to an individual in the same or a different country. In additional or further embodiments, data from any step of any method described herein (including characterization of melanoma in situ and/or invasive melanoma, information regarding cellular material such as DNA, RNA, and protein as well as transformed data, e.g. a molecular signature, from cellular material) is transferred to and/or received from a facility located within the same or different countries, including analysis of a data input, such as cellular material, performed in one facility in a particular location and corresponding data transmitted to another location, or directly to an individual, such as data related to the diagnosis, prognosis, responsiveness to therapy, or the like, in the same or different location or country.

[00271] Further System Embodiments

[00272] (1) A computer system for evaluating a sample from a subject, the system comprising: a) a central computing environment; b) an input device operatively connected to said central computing environment, wherein said input device is configured to receive a presence or absence of a genotype that correlates with a disease state in the sample; c) a trained algorithm executed by said central computing environment, wherein the trained algorithm is configured to use the presence or absence of the genotype to classify said sample as a disease or normal sample; and d) an output device operatively connected to said central computing environment, wherein said output device is configured to provide information on the classification to a user. (2) The computer system of embodiment 1, wherein the disease state comprises an inflammatory disease or condition. (3) The computer system of embodiment 1 or embodiment 2, wherein the disease state an inflammatory bowel disease or a subclinical phenotype thereof. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g. , ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (4) The computer system of any previous embodiment, wherein the sample comprises whole blood, plasma, serum, or tissue. (5) The computer system of any previous embodiment, wherein the genotype comprises rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs467640l, rs2975786, rs4676346 , rs6437356, rs6745 l85, rs4676407, rs2953 l56, rs4335944 , rs73999973, rs46764l0 , rs4676405, rs2953154, rs6732874, rs55862430, rsl262l598, rs55919442 , rs74991608, rs34826997, rs6437364, rs20H743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62l86545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs297578l, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs75567l2, rsl 14041303, rs6749767, rsl 15286046, rsl0l98255, rs62l87771, rsl0203408, rs4676391, rs6753653, rs7587l79, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl l33726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, rs78571781, or a genotype comprising a single nucleotide polymorphism in linkage disequilibrium therewith, and/or a sequence selected from SEQ ID NOS: 1-124. (6) The computer system of any previous embodiment, wherein the genotype comprises at least one of a polymorphism selected from (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an “A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs4676401, (xiv) a“G” allele in rs2975786, (xv) an“A” allele in rs4676346, (xvi) an“A” allele in rs6437356, (xvii) a“C” allele in rs6745185, (xviii) a“G” allele in rs4676407, (xix) a“G” allele in rs2953156, (xx) a“C” allele in rs4335944, (xxi) an“A” allele in rs73999973, (xxii) an“A” allele in rs4676410, (xxiii) a“G” allele in rs4676405, (xxiv) a“G” allele in rs2953154, (xxv) an“A” allele in rs6732874, (xxvi) a“G” allele in rs55862430, (xxvii) an“A” allele in rs l2621598, (xxviii) an“A” allele in rs55919442, (xxix) an“A” allele in rs74991608, and (xxx) a“T” allele in rs34826997. (7) The computer system of any previous embodiment 5-9, where linkage disequilibrium (LD) is defined by an r² value of at least 0.80, 0.85, 0.90, 0.95, or 1.0. (8) The computer system of any previous embodiment, wherein the genotype is associated with a risk that a subject has, or will develop, the disease state by a P value of at most about 1.0 x 10 ⁶, about 1.0 x 10 ⁷, about 1.0 x 10 ⁸, about 1.0 x 10^~9, about 1.0 x 10 ¹⁰, about 1.0 x 10 ²⁰, about 1.0 x 10 ³⁰, about 1.0 x 10^~4°, about 1.0 x 10 ⁵⁰, about 1.0 x 10 ⁶⁰, about 1.0 x 10 ⁷⁰, about 1.0 x 10^~8°, about 1.0 x 10 ⁹⁰, or about 1.0 x 10 ¹⁰⁰. (9) The computer system of any previous embodiment, wherein said output device provides a report summarizing said information on said classification. (10) The computer system of any previous embodiment, wherein said report comprises a recommendation for treatment of said disease state. (11) The computer system of embodiment 10, wherein the treatment comprises administration of modulator of GPR35 activity or expression. (12) The computer system of embodiment 1 1, wherein the modulator of GPR35 activity or expression comprises an antibody or antigen -binding fragment, peptide, or small molecule. (13) The computer system of embodiment 11, wherein the modulator of GPR35 comprises a compound of Formula I-XXVI. ( 14) The computer system of any preceding embodiment, wherein said genotype is determined with an assay comprising polymerase chain reaction (PCR), quantitative reverse-transcription PCR (qPCR), automated sequencing, genotype array, or a combination thereof.

[00273] ( 15) Use of a composition comprising one or more binding agents for generating a report that classifies a sample from a subject as disease or non-disease state, wherein the one or more binding agents specifically bind to at least one of SEQ ID NOS: 1-124. (16) The use of embodiment 15, wherein generating the report further comprises: (a) providing the sample from the subject; (b) assaying the sample from the subject for detecting the presence of the one or more polymorphisms in one or more genes; (c) generating the report based on the result of step (b); and (d) determining whether said subject has or is likely to have the disease based on the results of step (b). (17) The use of embodiment 15 or 16, wherein the disease state comprises an inflammatory bowel disease or a subclinical phenotype thereof. (18) The use of embodiments 15-17, wherein the disease state comprises inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), or a subclinical phenotype thereof. For example, the subclinical phenotype comprises stricturing, non- stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g. , ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. ( 19) The use of any of embodiments 15-18, wherein the sample comprises whole blood, plasma, serum, or tissue. (20)The use of embodiment 16, wherein assaying the sample from the subject for detecting the presence of the one or more polymorphisms of step (b) comprises: (i) contacting the sample with the one or more binding agents that specifically bind to the one or more polymorphisms; and (ii) determining whether the sample specifically binds to said one or more binding agents, wherein binding of the sample to the one or more binding agents indicates the presence of the polymorphism in the subject. (21) The use of embodiment 16, wherein assaying the sample from the subject for detecting the presence of the one or more polymorphisms of step (b) comprises sequencing of the sample. (22) The use of embodiment 16, wherein assaying the sample from the subject for detecting the presence of the one or more polymorphisms of step (b) comprises quantifying the amount of DNA comprising the at least one of SEQ ID NOS: 1-124. (23)The use of embodiment 22, wherein the quantifying comprises PCR. (24) The use of embodiment 23, wherein the PCR comprises real-time PCR. (25) The use of embodiment 22, wherein the quantifying comprises hybridization.

[00274] (26) A composition comprising one or more binding agents that specifically bind to at least one of (i) rsl l3435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl l33726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, (ii) a sequence selected from SEQ ID NOS: 1-31, (iii) a sequence selected from SEQ ID NOS: 32-62, (iv) a sequence selected from SEQ ID NOS: 63-101, (v) a sequence selected from SEQ ID NOS: 102-124, or (v) or a combination of (i)-(iv); wherein the one or more binding agents are selected to classify a sample as disease or non -disease of a disease state. (27) The composition of embodiment 26, wherein the one or more binding agents comprise oligonucleotides. (28)The composition of embodiment 27, wherein the oligonucleotides comprise RNA or DNA. (29)The composition of embodiment 27, wherein the one or more binding agents comprise aptamers, antibodies, peptide nucleic acids, or pyranosyl RNA.

[00275] (30) A kit for detecting an inflammatory disease or condition, the kit comprising: (a) at least one binding agent that specifically binds to at least one of (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, (ii) a sequence selected from SEQ ID NOS: 1-31, (iii) a sequence selected from SEQ ID NOS: 32-62, (iv) a sequence selected from SEQ ID NOS: 63-101, (v) a sequence selected from SEQ ID NOS: 102-124, or (v) or a combination of (i)-(iv); wherein the at least one binding agent is selected to detect a disease or non-disease state; and (b) reagents for detecting binding of said at least one binding agent to a DNA sample from a subject. (31) The kit of embodiment 30, wherein the at least one binding agent comprises at least one oligonucleotide. (32) The kit of embodiment 30, wherein the at least one binding agent comprises at least one aptamer, antibody, peptide nucleic acid, or pyranosyl RNA. (33) The kit of embodiments 30-32, wherein the at least one binding agent is labelled with a detectable label. (34) The kit of embodiment 30-33 wherein the at least one binding agent is immobilized to a surface.

[00276] (35) A system for generating a report that classifies a sample a disease or non-disease of a disease state, comprising: (a) a computer system that; (i) generates a molecular profile of a DNA sample based upon the presence of at least one polymorphism, or their complement; and (ii) generates a report that classifies the sample based on said molecular profile; and (b) a computer screen that displays said report. (36) The system of embodiment 35, wherein the presence of the at least one polymorphism is based on the result of an assay of said DNA sample, which result is entered into a database. (37) The system of embodiment 35 or 36, further comprising an input for said result. (38) The system of embodiments 35-37, wherein the at least one polymorphism is selected from (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648,

rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs674424l, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl093362l, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl l33726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, (ii) a sequence selected from SEQ ID NOS: 1-31, (iii) a sequence selected from SEQ ID NOS: 32-62, (iv) a sequence selected from SEQ ID NOS: 63-101, (v) a sequence selected from SEQ ID NOS: 102-124, or (v) or a combination of (i)-(iv).

[00277] Labeling

[00278] Systems and kits disclosed herein may comprise a protein, polypeptide, nucleic acid, or fragment thereof that is detectably labeled. Similarly, methods disclosed herein may comprise labeling a protein, polypeptide, nucleic acid, or fragment thereof, or use of a protein, polypeptide, nucleic acid, or fragment thereof that is detectably labeled. In some instances, the protein, polypeptide, nucleic acid, or fragment thereof is ligated to an adaptor and the adapter is detectably labeled. The detectable label may comprise a fluorescent label, e.g., by incorporation of nucleotide analogues. Other labels suitable for use in the present invention include, but are not limited to, biotin, iminobiotin, antigens, cofactors, dinitrophenol, lipoic acid, olefmic compounds, detectable polypeptides, electron rich molecules, enzymes capable of generating a detectable signal by action upon a substrate, and radioactive isotopes.

[00279] In some instances, the detectable label is a radioactive isotope. Radioactive isotopes by way of non-limiting example, include ³²P and ¹⁴C. Fluorescent molecules suitable for the present invention include, but are not limited to, fluorescein and its derivatives, rhodamine and its derivatives, texas red, 5’carboxy-fluorescein (“FAM”), 2’, 7’-dimethoxy-4’, 5’-dichloro-6-carboxy-fluorescein (“JOE”), N, N, N’, N’-tetramethyl-6-carboxy-rhodamine ( TAMRA ). 6-carboxy-X-rhodamine (“ROX”), HEX, TET, IRD40, and IRD41.

[00280] Fluorescent molecules which are suitable for use with systems, kits and methods disclosed herein include: cyamine dyes, including but not limited to Cy2, Cy3, Cy3.5, CY5, Cy5.5, Cy7 and FLUORX; BODIPY dyes including but not limited to BODIPY-FL, BODIPY-TR, BODIPY-TMR, BODIPY-630/650, and BODIPY -650/670; and ALEXA dyes, including but not limited to ALEXA - 488, ALEXA -532, ALEXA-546, ALEXA -568, and ALEXA-594; as well as other fluorescent dyes which will be known to those who are skilled in the art. Electron rich indicator molecules suitable for the present invention include, but are not limited to, ferritin, hemocyanin and colloidal gold.

[00281] Two-color fluorescence labeling and detection schemes may also be used (Shena et ak, 1995, Science 270:467-470). Use of two or more labels can be useful in detecting variations due to minor differences in experimental conditions (e.g. , hybridization conditions). In some embodiments of the invention, at least 5, 10, 20, or 100 dyes of different colors can be used for labeling. Such labeling would also permit analysis of multiple samples simultaneously which is encompassed by the invention.

[00282] Labeled molecules may be are contacted to a plurality of oligonucleotide probes under conditions that allow sample nucleic acids having sequences complementary to the probes to hybridize thereto (e.g., an array or chip). Depending on the type of label used, the hybridization signal may be detected using methods well known to those of skill in the art including, but not limited to, X-Ray film, phosphor imager, or CCD camera. When fluorescently labeled probes are used, the fluorescence emissions at each site of a transcript array may be detected by scanning confocal laser microscopy. In one embodiment, a separate scan, using the appropriate excitation line, is carried out for each of the two fluorophores used. In some instances, a laser is used that allows simultaneous specimen illumination at wavelengths specific to the two fluorophores and emissions from the two fluorophores may be analyzed simultaneously (see Shalon et al. (1996) Genome Res. 6, 639-645). In some instances, the arrays are scanned with a laser fluorescence scanner with a computer controlled X-Y stage and a microscope objective. Sequential excitation of the two fluorophores is achieved with a multi-line, mixed gas laser, and the emitted light is split by wavelength and detected with two photomultiplier tubes. Such fluorescence laser scanning devices are described, e.g. , in Schena et al. (1996) Genome Res. 6, 639-645. Alternatively, a fiber-optic bundle can be used such as that described by Ferguson et al. (1996) Nat. Biotech. 14, 1681-1684. The resulting signals can then be analyzed to determine the expression of GPR35 and housekeeping genes, using computer software.

[00283] In other embodiments, where genomic DNA of a subject is fragmented using restriction endonucleases and amplified prior to analysis, the amplification can comprise cloning regions of genomic DNA of the subject. In such methods, amplification of the DNA regions is achieved through the cloning process. For example, expression vectors can be engineered to express large quantities of particular fragments of genomic DNA of the subject (Sambrook and Russel, Molecular Cloning: A Laboratory Manual 4^th ed , Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012)).

[00284] In yet other embodiments, where the DNA of a subject is fragmented using restriction endonucleases and amplified prior to analysis, the amplification comprises expressing a nucleic acid encoding a gene, or a gene and flanking genomic regions of nucleic acids, from the subject. RNA (pre-messenger RNA) that comprises the entire transcript including introns is then isolated and used in the methods of the invention to analyze and provide a genetic signature of a cancer. In certain embodiments, no amplification is required. In such embodiments, the genomic DNA, or pre-RNA, of a subject may be fragmented using restriction endonucleases or other methods. The resulting fragments may be hybridized to SNP probes. Typically, greater quantities of DNA are needed to be isolated in comparison to the quantity of DNA or pre-mRNA needed where fragments are amplified. For example, where the nucleic acid of a subject is not amplified, a DNA sample of a subject for use in hybridization may be about 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1000 ng of DNA or greater. Alternatively, in other embodiments, methods are used that require very small amounts of nucleic acids for analysis, such as less than 400 ng, 300 ng, 200 ng, 100 ng, 90 ng, 85 ng, 80 ng, 75 ng, 70 ng, 65 ng, 60 ng, 55 ng, 50 ng, or less, such as is used for molecular inversion probe (MIP) assays. These techniques are particularly useful for analyzing clinical samples, such as paraffin embedded formalin-fixed material or small core needle biopsies, characterized as being readily available but generally having reduced DNA quality (e.g., small, fragmented DNA) and/or not providing large amounts of nucleic acids.

[00285] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.

EXAMPLES

Example 1. GPR35 SNPs Significantly Correlated with Crohn’s Disease and time to First Surgery

[00286] Genotyping data was produced from a Cedars-Sinai cohort of patients diagnosed with Crohn’s disease (CD) who underwent a first surgery, characterized by a number of days between a first diagnosis of CD and the first surgery (n=1091), and patients diagnosed with Crohn’s disease who did not undergo a first surgery. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi-hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Time to first and second surgery was calculated using Cox Proportional Hazards Regression analysis (PLINK). Table 2 shows SNPs that were significantly correlated with a time to first surgery in subjects with CD. The allele conferring risk within rsl 13435444 comprises a G. The allele conferring risk within rs4676406 comprises an A. The allele conferring risk within rs4676399 comprises a C The allele conferring risk within rs2975782 comprises an A. The allele conferring risk within rs3749172 comprises a C. The allele conferring risk within rs79844648 comprises a G. The allele conferring risk within rs6437356 comprises an A. The allele conferring risk within rs4676346 comprises an A. The allele conferring risk within rs4676401 comprises an A. The allele conferring risk within rs2975786 comprises a G. The allele conferring risk within rs6745185 comprises a C a. The allele conferring risk within rs4676407 comprises a G. The allele conferring risk within rs2953156 comprises a G. The allele conferring risk within rs4335944 comprises a C. The allele conferring risk within rs4676396 comprises an A at. The allele conferring risk within rs6735672 comprises an A. The allele conferring risk within rs4676402 comprises a. The allele conferring risk within rs2975780 comprises an Althea allele conferring risk within rs4676405 comprises a G. The allele conferring risk within rs2953154 comprises a G. The allele conferring risk within rs6732874 comprises an A. The allele conferring risk within rs55862430 comprises a G. The allele conferring risk within rsl2621598 comprises an A at. The allele conferring risk within rs55919442 comprises an A. These SNPs are considered predictive of a severe form of CD characterized by a faster progression to a first surgery as compared to an individual who does not express the SNP.

Table 2. GPR35 SNPs Significantly Correlated with Crohn’s Disease and time to First Surgery

Example 2 GPR35 SNPs Significantly Correlated with Crohn’s Disease and time to Second Surgery

[00287] Genotyping data was also produced from a Cedars-Sinai cohort patients diagnosed with CD who underwent a second surgery, characterized by a number of months between the first surgery and a second surgery(n=183), and patients diagnosed with CD who did not. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity -by- descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Genotyping data was produced from a Cedars-Sinai cohort of patients diagnosed with inflammatory bowel disease (IBD) and healthy patients without IBD as described in Example 1 (n=181). Table 3 shows SNPs that were significantly correlated with a second surgery in subjects with CD. The allele conferring risk within rsl 13435444 comprises a G. The allele conferring risk within rs79844648 comprises a G. The allele conferring risk within rs34228697 comprises an A. The allele conferring risk within rs74991608 comprises an A. The allele conferring risk within rs74991608 comprises an G. These SNPs are considered predictive of a severe form of CD characterized by a faster progression to a second surgery as compared to an individual who does not express the SNP.

Table 3. GPR35 SNPs Significantly Correlated with Crohn’s Disease and time to Second Surgery

Example 3. GPR35 SNPs Significantly Correlated with Inflammatory Bowel Disease ( IBP)

[00288] Genotyping data was produced from a Cedars-Sinai cohort of patients diagnosed with an inflammatory bowel disease (IBD) (n=9365) and healthy patients without IBD in a case control study. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴;

missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Table 4 shows SNPs that were significantly correlated IBD. Table 5 shows additional SNPs that are significantly correlated with IBD that is replicated in the large International IBD Genetic Consortium (IIBDGC) cohort (n> 200,000,000). Results show that rs3749171A, rs73999973A, and rsl368222G are strongly associated with inflammatory bowel disease. These SNPs are predictive of IBD in general.

Table 4. GPR35 SNPs Significantly Correlated with Inflammatory Bowel Disease (IBD) (Cedars-Sinai Cohort)

Table 5. GPR35 SNPs Significantly Correlated with Inflammatory Bowel Disease (IBD)

(IIBDGC Cohort)

[00289] Genotyping data was produced from a Cedars-Sinai cohort of patients diagnosed with Crohn’s disease (CD) (n=7,9669) and healthy patients without CD in case control studies. .

Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10⁴;

missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Table 6 shows SNPs that were significantly correlated with CD. Table 7 shows data from the Cedars-Sinai cohort replicated in the large International IBD Genetic Consortium (IIBDGC) cohort (n> 200,000,000). Results show that rs3749171A, rs73999973A, rs4676406A, rs2975786G, rs4676410A, and rs34826997T are strongly associated with Crohn’s disease.

Table 6. GPR35 SNPs Significantly Correlated with Crohn’s Disease (CD) (Cedars-Sinai Cohort)

Table 7. GPR35 SNPs Significantly Correlated with Crohn’s Disease (CD) (IIBDGC Cohort)

[00290] Genotyping data was produced from a Cedars-Sinai cohort of patients diagnosed with an ulcerative colitis (UC) (n=9862) and healthy patients without UC in a case control study. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Table 8 shows SNPs that were significantly correlated with UC. Table 9 shows data from the Cedars-Sinai cohort replicated in the large International IBD Genetic Consortium (IIBDGC) cohort (n> 200,000,000). Results show that rs3749171A, rs73999973A, rs4676406A, rs2975786G, rs4676410A, rs6437364A, rs4676407G, rs6745185C, rs2953156G, rs6437356A, and rs4335944C, are strongly associated with ulcerative colitis.

Table 8. GPR35 SNPs Significantly Correlated with Ulcerative Colitis (UC) (Cedars-Sinai)

Table 9. GPR35 SNPs Significantly Correlated with Ulcerative Colitis (UC) (IIBDGC Cohort)

Example 4. Small Bowel Expression Quantitative Trait Loci Mapping (SB-cOTL)

[00291] Genotyping data was produced from resected small bowel tissue samples from patients diagnosed with IBD and healthy patients without IBD. eQTL mapping was performed on these samples. Transcriptomic data was generated on small bowel tissue. Briefly, uninflamed tissue from formalin-fixed paraffin-embedded (FFPE) small bowel resection margins of 100 subjects requiring surgery at Cedars-Sinai Medical Center for Crohn’s disease was identified. Whole-thickness ileal tissue was scraped from the FFPE tissue sections followed by RNA extraction using the RNeasy FFPE kit (Qiagen) according to the manufacturer's instructions. The Transplex Whole Transcriptome Amplification kit (WTA2; Sigma) was used for cDNA synthesis and amplification. Subsequent purification of the cDNA product was performed with the PCR Purification kit (Qiagen). Sample quality was confirmed using the Agilent Bioanalyzer. For samples passing quality control, Cy5 labeling with the ULST Fluorescent Labeling kit (Kreatech) and hybridization (performed in duplicate for each sample) to Whole Human Genome 4x44k Microarrays (Agilent) was performed. [00292] Single channel microarray expression data extracted using Agilent feature extraction software was received from Genome Technology Access Center at Washington University in St. Louis. Raw expression data available in technical duplicates was normalized using LIMMA package implemented in R version 3.2.2. The expression data preprocessing included background correction of the expression data, followed by log2 -transformation and quantile-normalization Unsupervised hierarchical clustering of expression data was used to remove outlier subjects. eQTL mapping was implemented in Matrix eQTL R package using the available expression and genotype data for n=85 independent Caucasian samples from patients undergoing surgery for small bowel disease and n=24 UC rectum tissues. Associations between genotype and probe expression level were performed using a linear regression model with additive genotype effects. All associations were adjusted for gender, age and population sub-structure using the first two principal components. Gene bounds were defined using a 1 Mb window around the transcription start position of given gene as obtained from UCSC Genome Browser. For cis-eQTL mapping, a 1Mb cis distance from gene bounds was used. Cis-eQTLs were defined as association signals from SNPs located within 1 Mb from each of the gene bounds. False discovery rates (FDR) were estimated to correct for multiple testing using Matrix eQTL according to the Benjamini and Hochberg method. Note that FDR calculation in matrix eQTL does not take into account“linkage disequilibrium” between the SNPs and may be overly stringent. A negative beta value indicates a decrease in GPR35 gene expression. A positive beta value indicates an increase in GPR35 gene expression. Results show that strong associations between rs3749l71A (P=8.00E-02; Beta = 0.205302614), rs4676399C ( =7.47E-02; Beta =0.212280786 ), rs2975782A (P=9.50E-02; Beta = 0.14199281), rs3749172C (P=9.50E-02; Beta = 0.14199281), and rs4676396A ( 7.45 L-02: Beta = 0.191332906), with increased GPR35 expression in the SB of patients diagnosed with IBD. Results also show that rs79844648G ( =9.30E-02; Beta = -0.262640037) is associated with decreased expression of GPR35 in the small bowel of patients diagnosed with IBD.

Example 5 Rectum Expression Quantitative Trait Loci Manning

[00293] Genotyping data was produced from resected rectum tissue samples from patients diagnosed with UC and healthy patients without UC. eQTL mapping was performed on these samples. SNP rs34228697 was associated with decreased expression of GPR35. Transcriptomic data was generated on rectum tissue. Briefly, uninflamed tissue from formalin-fixed paraffin-embedded (FFPE) rectum resection margins of 100 subjects requiring surgery at Cedars-Sinai Medical Center for Crohn’s disease was identified. Whole-thickness rectal tissue was scraped from the FFPE tissue sections followed by RNA extraction using the RNeasy FFPE kit (Qiagen) according to the manufacturer's instructions. The Transplex Whole Transcriptome Amplification kit (WTA2; Sigma) was used for cDNA synthesis and amplification. Subsequent purification of the cDNA product was performed with the PCR Purification kit (Qiagen). Sample quality was confirmed using the Agilent Bioanalyzer. For samples passing quality control, Cy5 labeling with the ULST Fluorescent Labeling kit (Kreatech) and hybridization (performed in duplicate for each sample) to Whole Human Genome 4x44k Microarrays (Agilent) was performed.

[00294] Single channel microarray expression data extracted using Agilent feature extraction software was received from Genome Technology Access Center at Washington University in St. Louis. Raw expression data available in technical duplicates was normalized using LIMMA package implemented in R version 3.2.2. The expression data preprocessing included background correction of the expression data, followed by log2 -transformation and quantile-normalization. Unsupervised hierarchical clustering of expression data was used to remove outlier subjects. eQTL mapping was implemented in Matrix eQTL R package using the available expression and genotype data for n=85 independent Caucasian samples from patients undergoing surgery for small bowel disease and n=24 UC rectum tissues. Associations between genotype and probe expression level were performed using a linear regression model with additive genotype effects. All associations were adjusted for gender, age and population sub-structure using the first two principal components. Gene bounds were defined using a 1 Mb window around the transcription start position of given gene as obtained from UCSC Genome Browser. For cis-eQTL mapping, a 1Mb cis distance from gene bounds was used. Cis-eQTLs were defined as association signals from SNPs located within 1 Mb from each of the gene bounds. False discovery rates (FDR) were estimated to correct for multiple testing using Matrix eQTL according to the Benjamini and Hochberg method. Note that FDR calculation in matrix eQTL does not take into account“linkage disequilibrium” between the SNPs and may be overly stringent. Results show that rs34228697A (P=9.60E-3; Beta = -1.82892028) is associated with a decrease in GPR35 expression in rectal tissue obtained from patients diagnosed with IBD.

Example 6 GPR35 SNPs Significantly Correlated with Serological Markers in Ulcerative Colitis (UC) Subjects

[00295] Genotyping data was collected from a Cedars-Sinai cohort of patients with ulcerative colitis (UC) and patients without UC. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi-hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. In addition, serum samples were obtained from all patients and tested for the presence of antibodies against Escherichia coli outer membrane porin C (anti-OmpC) and antibodies against Saccharomyces cerevisiae (ASCA). Results showed that the presence of anti-OmpC and ASCA correlated with SNPs in the GPR35 locus as shown in Table 10. A negative beta value indicates a decrease in expression of the serological marker. A positive beta values indicates an increase in expression of the serological marker. The presence of anti-OmpC or ASCA, in addition to at least one of the SNPs of Table 10 is predictive of a risk of a subject developing UC. The allele conferring risk within rs3749171 comprises an A. The allele conferring risk within rs4676399 comprises a C. The allele conferring risk within rs2975782 comprises an A. The allele conferring risk within rs3749172 comprises a C. The allele conferring risk within rs4676402 comprises an A. The allele conferring risk within rs4676346 comprises an A.

Table 10. GPR35 SNPs Significantly Correlated with Serological Markers in Ulcerative Colitis

(UC) Subjects

Example 7 GPR35 SNPs Significantly Correlated with Serological Markers in Crohn’s Disease Subjects

[00296] Genotyping data was collected from a Cedars-Sinai cohort of patients with Crohn’s Disease (CD) and patients without CD. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi-hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. In addition, serum samples were obtained from all patients and tested for the presence of antibodies against Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA). Results showed that the presence of ASCA and ANCA correlated with SNPs in the GPR35 locus as shown in Table 11. The presence of ASCA or ANCA, in addition to one of the SNPs of Table 11 is predictive of a risk of a subject developing CD. The risk allele within rs4676406 comprises an A. The risk allele within rs2975780 comprises an A. The risk allele within rs4676346 comprises an A.

Table 11. GPR35 SNPs Significantly Correlated with Serological Markers ANCA and ASCA in

Crohn’s Disease (CD) Subjects

Example 8 GPR35 SNPs Significantly Correlated with Pancolitis and/or Left-Sided Colitis

[00297] Genotyping data was collected from patients diagnosed with ulcerative colitis (UC) with pancolitis or left-sided colitis and UC patients without pancolitis or left-sided colitis. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity -by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Results showed that the SNPs in the GPR35 listed in Tables 12 and 13, respectively, are associated with pancolitis and/or left-sided colitis in subjects with UC. The allele conferring risk within rs4676402 comprises an A. The allele conferring risk within rs6735672 comprises an A. The allele conferring risk within rs4676399 comprises a C. The allele conferring risk within rs4676396 comprises an A. Table 12. GPR35 SNPs Significantly Correlated with Pancolitis in Ulcerative Colitis (UC) Subjects

Table 13. GPR35 SNPs Significantly Correlated with Left-sided Colitis in UC Subjects

Example 9. GPR35 SNPs Significantly Correlated with Anti-TNF Non-Response

[00298] Genotyping data was collected from patients with IBD (n=429), UC (n=131), or CD (n=281) who suffer from primary non-response to induction of an anti-TNF therapy, and patients with IBD,

UC, or CD who respond to the induction of the anti-TNF therapy. Genotyping data was collected from patients with UC (n=99), or CD (n=243) who suffer from secondary loss of response to an anti-TNF therapy, and patients with IBD, UC, or CD who respond do not suffer from a loss of response. Anti- TNF non-response is characterized by either primary non-response or secondary non-response. Primary non-response refers to a subject not responding to the induction of an anti-TNF therapy. Secondary non-response, or loss of response, refers to the loss of response during maintenance after a successful induction of the anti-TNF therapy. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy- Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis.

Results showed SNPs at the GPR35 locus provided in Tables 14 and 15 are associated with anti-tumor necrosis factor (TNF) non-response. Table 14. GPR35 SNPs Significantly Correlated with Anti-TNF Non-Response (Primary Nonresponse v. Primary Response)

Table 15. GPR35 SNPs Significantly Correlated with Anti-TNF Non-Response (Time to Loss of Response)

Example 10. SNPs Associated with Arthralgia in Crohn’s Disease Subjects

[00299] Genotyping data was collected from a Cedars-Sinai cohort of patients diagnosed with Crohn’s disease (CD) with arthralgia (n=99). Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy- Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Results show that SNPs at the GPR35 locus provided in Table 16 are significantly associated with arthralgia in CD patients.

Table 16. GPR35 SNPs Significantly Correlated with Crohn' Disease and Arthralgia

Example 11. SNPs Associated with Stricturing or Stricturing and Penetrating Phenotype

[00300] Genotyping data was collected from a Cedars-Sinai cohort of patients diagnosed with Crohn’s disease (CD) with stricturing (n=2905) and stricturing and penetrating (n=6064) disease. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Results showed that SNPs at the GPR35 locus provided in Tables 17-18 are associated with Stricturing disease phenotype and stricturing and penetrating disease phenotypes. The SNPs in Tables 17-18 are predictive of these subclinical phenotypes in CD patients.

Table 17. GPR35 SNPs Significantly Correlated with Crohn's Disease (CD) and Stricturing Phenotype

Table 18. GPR35 SNPs Significantly Correlated with CD and Stricturing and Penetrating

Phenotype

Example 12 SNPs Associated with Disease Location

[00301] Genotyping data was collected from a Cedars-Sinai cohort of patients diagnosed with Crohn’s disease (CD) isolated to the ileum (n=3008), colon (n=5634), ileocolonic region of the intestine (n=2126), and upper gastro-intestinal (GI) tract (n=2008). Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Results showed that SNPs at the GPR35 locus provided in Tables 19-22 are significantly associated with isolated disease in the ileum, colon ileocolonic region of the intestine, and upper GI tract, respectively.

Table 19. GPR35 SNPs Significantly Correlated with Crohn's Disease (CD) Isolated to the Ileum

Table 20. GPR35 SNPs Significantly Correlated with Crohn's Disease Isolated to the Colon

Table 21. GPR35 SNPs Significantly Correlated with Crohn's Disease Isolated to Ileocolonic Region

Table 22. GPR35 SNPs Significantly Correlated with Crohn's disease and upper GI disease

Example 13. GPR35 SNPs Significantly Correlated with Morphological Defects of Ileal Paneth Cells

[00302] Genotyping data was collected from patients with Crohn’s Disease (CD) with morphological defects of ileal Paneth cells, as determined using the classification set forth in VanDussen et al., “Genetic Variants Synthesize the Produce Paneth Cell Phenotypes That Define Subtypes of Crohn’s Disease,” Gastroenterology 2014; 146:200-209. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi-hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Results showed that SNPs at the GPR35 locus provided in Table 23 are associated with morphological defects of ileal Paneth cells in CD subjects. Table 23. GPR35 SNPs Significantly Correlated with Crohn's Disease and Morphological Defects of Ileal Paneth Cells

Example 14. GPR35 SNPs Significantly Correlated with Poor Drug Metabolism in CD Subjects

[00303] Genotyping data was collected from patients diagnosed with Crohn’s disease (CD) who suffer from poor drug metabolism (PDM). Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy- Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis.

Results showed that SNPs at the GPR35 locus provided in Table 24 are associated with poor drug metabolism.

Table 24. GPR35 SNPs Significantly Correlated with Crohn's Disease and Poor Drug

Metabolism

Example 15 GPR35 SNPs Significantly Correlated with Perianal Crohn’s Disease (pCD)

[00304] Genotyping data was collected from patients with perianal Crohn’s disease (pCD) (n=10,738). Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴;

missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis Results showed that SNPs at the GPR35 locus provided in Table 26 are associated with pCD. The allele conferring risk within rsl 13435444 comprises a G. The allele conferring risk within rs34228697 comprises an A.

Table 25. GPR35 SNPs Significantly Correlated with Perianal Crohn's Disease

Example 16. GPR35 SNPs Significantly Correlated with Medically Refractory Ulcerative Colitis (mrUC)

[00305] Genotyping data was collected from patients with ulcerative colitis (UC) with medically refractory ulcerative colitis (mrUC), and subjects with UC without mrUC (n=l 1,022). mrUC refers to the failure of a standard treatment to induce remission of UC. Genotyping was performed at Cedars- Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Results showed that SNPs at the GPR35 locus provided in Table 26 are associated with mrUC.

Table 26. GPR35 SNPs Significantly Correlated with Medically Refractory Ulcerative Colitis (mrUC) (mrUC v. non-mrUC)

[00306] Genotyping data was collected from patients with mrUC with a time to first colectomy as defined as the time between a first diagnosis and a first colectomy (n=6,326). Time to first colectomy comprises between about 20-65, with the fewer number of months indicating the high risk of complicated disease behavior. Results show that SNPs at the GPR35 locus provided in Table 27 are associated with time to first colectomy in subjects with mrUC that is shorter as compared to a subject that does not express the SNPs provided in Table 28. Table 27. GPR35 SNPs Significantly Correlated with Medically Refractory Ulcerative Colitis

(mrUC) and Time to First Colectomy

[00307] Genotyping data was collected from a Cedars-Sinai cohort of patients with mrUC with a time to first colectomy that is less than 60 months, and patients with mrUC with a time to first colectomy that is more than 60 months (n=3,931). Results showed that SNPs at the GPR35 locus provided in Table 28 are associated with a time to first colectomy that is less than 60 months from first diagnosis of UC as compared to a subject with UC that does not require a colectomy in less than 60 months.

Table 28. GPR35 SNPs Significantly Correlated with mrUC and Time to First Colectomy (<60 months v. >60 months)

Example 17 GPR35 SNPs Associated with Spondylitis (Bcchtcrcw^’s Disease)

[00308] Genotyping data was collected from patients with Crohn’s disease (CD) suffering from Spondylitis (n= 1,797). Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p < 10 ⁴; missingness in SNPs of >2%; minor allele frequency < 1%. Related individuals (Pi-hat scores >0.25) were identified using identity -by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion <0.75) were included in the analysis. Results showed that SNPs at the GPR35 locus provided in Table 29 are associated with Spondylitis.

Table 29. SNPs Associated with Crohn's Disease and Spondylitis (Bechterew's disease)

Example 18. Treating an Inflammatory Bowel Disease

[00309] A moderate to severe form of an inflammatory bowel disease, including Crohn’s disease and/or ulcerative colitis, is treated with a therapeutically effective amount of an activator of GPR35 activity or expression in a subject, provided the subject is determined to have a GPR35 risk genotype. Optionally, the subject is, or is susceptible to be, non-responsive to certain therapies such as anti-TNF, steroids, or immunomodulators, such as those disclosed herein. A sample of whole blood is obtained from the subject. An assay is performed on the sample obtained from the subject to detect a presence or absence of the GPR35 risk genotype comprising rsl 13435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A, by Illumina Immuno Array or polymerase chain reaction (PCR) under standard hybridization conditions.

[00310] The subject is determined to be suitable for treatment with an activator of GPR35 activity or expression if the genotype is detected in the sample obtained from the subject. A therapeutically effective amount of an activator of GPR35 activity or expression is administered to the subject, provided the subject is determined to have the genotype.

Example 19. Phase 1A Clinical Trial

[00311] A phase 1A clinical trial is performed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a compound of any one of Formula I - XXVI in subjects with moderately to severely active Crohn’s disease. Eligible subjects are men and women 18 years and older. Optionally, two groups of subjects are selected: (i) subjects having a genotype comprising one or more of rsl 13435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A; and (ii) subjects lacking the genotype.

[00312] Inclusion Criteria: Eligible subjects are men and women 18 years and older. Two groups of subjects are selected: (i) subjects having a genotype comprising one or more of rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A; and (ii) subjects lacking the genotype. Subjects are patients with Crohn's disease of at least 3 months' duration, confirmed at any time in the past by radiography, histology, and/or endoscopy. Female patient of childbearing potential must have a negative highly sensitive serum (beta-human chorionic gonadotropin [b-hCG]) pregnancy test result at screening and a negative urine pregnancy test result at Week 0. Subjects must adhere to the following requirements for concomitant medication for the treatment of Crohn's disease, which are permitted provided that doses meeting these requirements are stable, or have been discontinued, for at least 3 weeks before baseline (Week 0), unless otherwise specified: a) Oral 5 -aminosalicylic acid (5-ASA) compounds, b) Oral corticosteroids at a prednisone-equivalent dose at or below 40 milligram per day (mg/day), or 9 mg/day of budesonide, or 5 mg/day beclomethasone dipropionate, c) Antibiotics being used as a primary treatment of Crohn's disease, d) Conventional immunomodulators (that is, azathioprine (AZA), 6-mercaptopurine (6-MP), or Methotrexate (MTX)): participants must have been taking them for at least 12 weeks and at a stable dose for at least 4 weeks before baseline.. Subjects who has or had extensive colitis for greater than or equal to (>=) 8 years, or disease limited to the left side of the colon for >= 12 years, must either have had a colonoscopy to assess for the presence of dysplasia within 1 year before the first administration of study agent or a colonoscopy to assess for the presence of malignancy at the screening visit, with no evidence of malignancy. Subjects must have active Crohn's disease, defined as a baseline Crohn's Disease Activity Index (CDAI) score of >= 220 but <= 450.

[00313] Experimental (Part I): Placebo. Subjects will receive placebo at Weeks 0, 2, 4, and 6. From Week 8 Placebo -treated subjects who are in clinical response at Week 8 (>^_ 100-point reduction from baseline in Crohn's Disease Activity Index (CDAI) or CDAI <150) will continue to receive placebo every 2 weeks from Week 8 through Week 12. Placebo-treated subjects who are not in clinical response at Week 8 will receive test compound (a compound described herein) 400 mg at Week 8 and then test compound every two weeks from Week 10 through Week 12.

[00314] Experimental (Part I): Placebo. Test Compound. Subjects will receive test compound 400 milligram (mg) at Week 0 then 200 mg every two weeks through Week 22.

[00315] Experimental (Part II): Placebo. Placebo at Weeks 0, 2, 4, and 8. From Week 12, placebo-treated subjects who are in clinical response at Week 8 (>=100-point reduction from baseline in CDAI or CDAI <150) will continue to receive placebo at Weeks 8, 10, and 12. Placebo-treated subjects who are not in clinical response at Week 8 will receive test compound 150 mg at Week 8 and then test compound 75 mg at Weeks 10, and 12.

[00316] Experimental (Part II): Test Compound High Dose. Test compound 400 mg at Week 0 and 200 mg at Weeks 2, 4, 8, and 12.

[00317] Experimental (Part II) Test Compound Middle Dose. Test compound 150 mg at Week 0 and 75 mg at Weeks 2, 4, 8, and 12.

[00318] Experimental (Part II) Test compound Low Dose. Test compound 50 mg at Week 0 and 25 mg at Weeks 2, 4, 8, and 12. [00319] Primary Outcome Measures: Part I: Change From Baseline in the Crohn's Disease Activity Index (CDAI) Score at Week 8 [Time Frame: Baseline through Week 8] - CDAI will be assessed by collecting information on 8 different Crohn's disease-related variables: extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being. The last 4 variables are scored over 7 days by the participant on a diary card. Part II: Change From Baseline in the Crohn's Disease Activity Index (CDAI) Score at Week 8 [Time Frame: Baseline through Week 8] - CDAI are assessed by collecting information on 8 different Crohn's disease-related variables: extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being. The last 4 variables are scored over 7 days by the participant on a diary card.

[00320] Secondary Outcome Measures: Part II: Clinical Remission at Week 8 as Measured by Crohn's Disease Activity Index (CDAI <150) [Time Frame: Week 8 ]. Part II: Clinical Response at Week 8 as Measured by CDAI (>= 100-point reduction from baseline in CDAI or CDAI <150) [Time Frame: Week 8]. Part II: Change in Patient-Reported Outcome (PRO)-2 from baseline at Week 8 [Time Frame: Baseline through Week 8] - The PRO-2 score is the sum of the abdominal pain and stool frequency subscores of the CDAI score. Part II: Clinical remission at Week 8 as measured by PRO-2 (PRO-2 <75) [Time Frame: Week 8]. Part II: Clinical response at Week 8 as measured by PRO-2 (>=50-point reduction from baseline in PRO-2 or PRO-2 <75) [Time Frame: Week 8]. Part II: Change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline at Week 12 [Time Frame: Baseline through Week 12] - The SES-CD score is based on the evaluation of 4 endoscopic components (presence/size of ulcers, proportion of mucosal surface covered by ulcers, proportion of mucosal surface affected by any other lesions, and presence/type of narrowing/strictures) across 5 ileocolonic segments. Each endoscopic component is scored from 0 to 3 for each segment, and a total score is derived from the sum of all the component scores (range, 0 to 56).

Example 20 Phase IB Clinical Trial

[00321] A phase IB clinical trial is performed to evaluate the efficacy of a compound described herein comprising an activator of GPR35 activity or expression of any one of Formulas I-XXVI in participants with moderately to severely active Crohn’s disease that have a genotype comprising one or more of rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A.

[00322] Experimental. 10 patients positive for rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A, are administered the activator of GPR35 activity or expression. 5-10 patients negative for rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs467640lA, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953 l56G, rs4335944C, rs73999973A, rs46764lOA, rs4676405G, rs2953 l54G, rs6732874A, rs55862430G, rsl262l598A, rs559l9442A, rs74991608A, rs34826997T, and/or rs6437364A, are administered the activator of GPR35 activity or expression. Patients are monitored in real-time. Central ready of endoscopy and biopsy is employed, with readers blinded to point of time of treatment and endpoints.

[00323] Inclusion Criteria: Two groups of subjects are selected: (i) subjects having rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs467640lA, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl262l598A, rs559l9442A, rs7499l608A, rs34826997T, and/or rs6437364A genotype, and (ii) subjects lacking rsl l3435444G, rs3749l71A, rs4676406A, rs4676399C, rs2975782A, rs3749l72C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs467640lA, rs2975786G, rs4676346A, rs6437356A, rs6745 l85C, rs4676407G, rs2953 l56G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953 l54G, rs6732874A, rs55862430G, rsl262l598A, rs559l9442A, rs7499l608A, rs34826997T, and/or rs6437364A genotype.

[00324] Primary Outcome Measures: Simple Endoscopic Score for Crohn’s Disease (SESCD), Crohn's Disease Activity Index (CDAI), and Patient Reported Outcome (PRO). If the rsl 13435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A genotype positive group shows at least 20% reduction from baseline, a Phase 2a clinical trial is performed.

[00325] Inclusion Criteria: PRO entry criteria: Abdominal pain score of 2 or more and/or stool frequency score of 4 or more. Primary outcome would be pain core of 0 or 1 and stool frequency score of 3 or less with no worsening from baseline. Endoscopy entry criteria: SESCD ileum only entry at score of 4 and 6 if colon is involved. Primary endoscopic outcome is 40-50% delta of mean SESCD. Example 21. Phase 2A Clinical Trial

[00326] A phase 2A clinical trial is performed to evaluate efficacy of a compound of any one of Formula I - XXVI in subjects having a genotype comprising rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745 l85C, rs4676407G, rs2953 l56G, rs4335944C, rs73999973A, rs46764lOA, rs4676405G, rs2953 l54G, rs6732874A, rs55862430G, rsl262l598A, rs55919442A, rs74991608A, rs34826997T, and/or rs6437364A, with moderately to severely active Crohn’s disease.

[00327] Experimental. 40 patients (drug and placebo groups) positive for rsl l3435444G, rs3749l71A, rs4676406A, rs4676399C, rs2975782A, rs3749l72C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs467640lA, rs2975786G, rs4676346A, rs6437356A, rs6745 l85C, rs4676407G, rs2953 l56G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953 l54G, rs6732874A, rs55862430G, rsl262l598A, rs559l9442A, rs74991608A, rs34826997T, and/or rs6437364A are administered the activator of GPR35 activity or expression or placebo for 12 weeks. An interim analysis is performed after 20 patients from each group are treated at the highest dose to look for 40-50% delta between placebo and treated group in primary outcome (at least 20% reduction from baseline in SESCD, CDAI, and PRO).

[00328] Primary Outcome Measures: Simple Endoscopic Score for Crohn’s Disease (SESCD), Crohn's Disease Activity Index (CDAI), and Patient Reported Outcome (PRO).

[00329] Inclusion Criteria: PRO entry criteria: Abdominal pain score of 2 or more and/or stool frequency score of 4 or more. Primary outcome would be pain core of 0 or 1 and stool frequency score of 3 or less with no worsening from baseline. Endoscopy entry criteria: SESCD ileum only entry at score of 4 and 6 if colon is involved. Primary endoscopic outcome is 40-50% delta of mean SESCD.

FURTHER EMBODIMENTS

[00330] (1) A method comprising: (a) obtaining a biological sample from a subject; (b) assaying for the presence of a single nucleotide polymorphism in a nucleic acid of the biological sample, the single nucleotide polymorphism comprising a risk allele within rsl 13435444, rs3749l7l, rs4676406, rs4676399, rs2975782, rs3749l72, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745 l85, rs4676407, rs2953 l56, rs4335944 , rs73999973, rs46764l0 , rs4676405, rs2953 l54, rs6732874, rs55862430, rsl2621598, rs559l9442 , rs7499l608, rs34826997, rs6437364, rs20H743, rs7908670l, rs674424l, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62l86545, rs754329, rsl093362l, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs297578l, rsl3019955, rs35 l55396, rs2060l88, rs2060l89, rsl0933624, rs6760l69, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0l98255, rs62l8777l, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a single nucleotide polymorphism in linkage disequilibrium therewith; and (c) administering a therapeutic agent that modifies at least one of GPR35 expression and GPR35 activity. (2) The method of embodiment 1, comprising detecting the presence of at least one single nucleotide polymorphism. (3) The method of embodiment 1, wherein the subject presents a symptom of an inflammatory bowel disease. (4) The method of embodiment 1, wherein the subject has been diagnosed with an inflammatory bowel disease. (5) The method of embodiment 1, comprising assaying for a presence of a serological marker in the subject. (6) The method of embodiment 5, wherein the serological marker is selected from an mti-Saccharomyces cerevisiae antibody (ASCA), an anti-neutrophil cytoplasmic antibody (ANCA), and E.coli outer membrane porin protein C (OmpC). (7) The method of embodiment 5 or 6, comprising quantifying the serological marker to obtain a quantity. (8) The method of embodiment 7, wherein quantity deviates with statistical significance from a reference quantity in a healthy control subject. (9) The method of embodiment 1, comprising assaying for the presence of at least two of the single nucleotide polymorphisms. (10) The method of embodiment 1, comprising assaying for the presence of at least three of the single nucleotide polymorphisms. (11) The method of embodiment 1, comprising assaying for the presence all of the single nucleotide polymorphisms. (12) The method of embodiment 1, wherein the single nucleotide polymorphism is rs2975780. (13) The method of embodiment 12, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs2975780. (14) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676396. (15) The method of embodiment 14, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs4676396. (16) The method of embodiment 1, wherein the single nucleotide polymorphism is rs6735672. (17) The method of embodiment 16, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs6735672. (18) The method of embodiment 1, wherein the single nucleotide polymorphism is rs34228697. (19) The method of embodiment 18, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs34228697. (20) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676401 (21) The method of embodiment 20, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs4676401. (22) The method of embodiment 1, wherein the single nucleotide polymorphism is rs2975786. (23) The method of embodiment 22, wherein the single nucleotide polymorphism has a risk allele of G in a sense strand of a DNA molecule encoding rs2975786. (24) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676346. (25) The method of embodiment 24, wherein the single nucleotide polymorphism has a allele of A in a sense strand of a DNA molecule encoding rs4676346. (26) The method of embodiment 1, wherein the at least one single nucleotide polymorphism is rs6437356. (27) The method of embodiment 26, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs6437356. (28) The method of embodiment 1, wherein the single nucleotide polymorphism is rs6745185. (29) The method of embodiment 28, wherein the single nucleotide polymorphism has a risk allele of C in a sense strand of a DNA molecule encoding rs6745185.

(30) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676407. (31) The method of embodiment 30, wherein the single nucleotide polymorphism has a risk allele of G in a sense strand of a DNA molecule encoding rs4676407. (32) The method of embodiment 1, wherein the single nucleotide polymorphism is rs2953156. (33) The method of embodiment 32, wherein the single nucleotide polymorphism has a risk allele of G in a sense strand of a DNA molecule encoding rs2953156. (34) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4335944. (35) The method of embodiment 34, wherein the single nucleotide polymorphism has a risk allele of C in a sense strand of a DNA molecule encoding rs4335944. (36) The method of embodiment 1, wherein the single nucleotide polymorphism is rs73999973. (37) The method of embodiment 36, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs73999973. (38) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676410. (39) The method of embodiment 38, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs4676410. (40) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676405. (41) The method of embodiment 40, wherein the single nucleotide polymorphism has a risk allele of G in a sense strand of a DNA molecule encoding rs4676405. (42) The method of embodiment 1, wherein the single nucleotide polymorphism is rs2953154. (43) The method of embodiment 42, wherein the single nucleotide polymorphism has a risk allele of G in a sense strand of a DNA molecule encoding rs2953154. (44) The method of embodiment 1, wherein the single nucleotide polymorphism is rs6732874. (45) The method of embodiment 44, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs6732874. (46) The method of embodiment 1, wherein the single nucleotide polymorphism is rs55862430. (47) The method of embodiment 46, wherein the single nucleotide polymorphism has a risk allele of G in a sense strand of a DNA molecule encoding rs55862430. (48) The method of embodiment 1, wherein the single nucleotide polymorphism is rsl2621598. (49) The method of embodiment 48, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rsl2621598. (50) The method of embodiment 1, wherein the single nucleotide polymorphism is rs55919442. (51) The method of embodiment 50, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs55919442. (52) The method of embodiment 1, wherein the single nucleotide polymorphism is rs74991608. (53) The method of embodiment 52, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs74991608. (54) The method of embodiment 1, wherein the single nucleotide polymorphism is rs34826997. (55) The method of embodiment 54, wherein the single nucleotide polymorphism has a risk allele of T in a sense strand of a DNA molecule encoding rs34826997. (56) The method of embodiment 1, wherein the single nucleotide polymorphism is rs6437364. (57) The method of embodiment 56, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs6437364. (58) The method of embodiment 1, wherein the single nucleotide polymorphism is rsl 13435444. (59) The method of embodiment 58, wherein the single nucleotide polymorphism has a risk allele of G in a sense strand of a DNA molecule encoding rsl 13435444. (60) The method of embodiment 1, wherein the single nucleotide polymorphism is rs3749171. (61) The method of embodiment 60, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs3749171. (62) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676406. (63) The method of embodiment 62, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs4676406. (64) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676399. (65) The method of embodiment 64, wherein the single nucleotide polymorphism has a risk allele of C in a sense strand of a DNA molecule encoding rs46763 9. (66) The method of embodiment 1, wherein the single nucleotide polymorphism is rs2975782. (67) The method of embodiment 66, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs2975782. (68) The method of embodiment 1, wherein the single nucleotide polymorphism is rs3749172. (69) The method of embodiment 68, wherein the single nucleotide polymorphism has a risk allele of C in a sense strand of a DNA molecule encoding rs3749172. (70) The method of embodiment 1, wherein the single nucleotide polymorphism is rs79844648. (71) The method of embodiment 70, wherein the single nucleotide polymorphism has a risk allele of G in a sense strand of a DNA molecule encoding rs79844648. (72) The method of embodiment 1, wherein the single nucleotide polymorphism is rs4676402. (73) The method of embodiment 72, wherein the single nucleotide polymorphism has a risk allele of A in a sense strand of a DNA molecule encoding rs4676402. (74) The method of embodiment 1, wherein the therapeutic agent is an agonist of GPR35. (75) The method of embodiment 74, wherein the single nucleotide polymorphism is effective to decrease expression of GPR35 or decreased activity of GPR35. (76) The method of embodiment 1, wherein the therapeutic agent is an antagonist of GPR35 (77) The method of embodiment 76, wherein the single nucleotide polymorphism results in increased expression of GPR35 or increased activity of GPR35. (78) The method of embodiment 1, wherein the therapeutic agent is an allosteric modulator of GPR35. (79) The method of embodiment 1, wherein the therapeutic agent is a small molecule that binds GPR35. (80) The method of embodiment 79, wherein the small molecule that binds GPR35 is a GPR35 agonist. (81) The method of embodiment 79 or embodiment 80, where the small molecule is selected from:

(82) The method of embodiment 79, wherein the small molecule that binds GPR35 is a GPR35 partial agonist. (83) The method of embodiment 79 or embodiment 82, where the small molecule is selected from:

(84) The method of embodiment 79, wherein the small molecule that binds GPR35 is a GPR35 antagonist. (85) The method of embodiment 79, wherein the small molecule that binds GPR35 is a GPR35 an inverse agonist. (86) The method of embodiment 79, 84, or 85, where the small molecule is selected from:

(87) The method of embodiment 1, wherein the therapeutic agent is a GPR35-binding antibody or GPR35-binding antibody fragment. (88) The method of embodiment 1, wherein the subject is human. (89) The method of embodiment 1, wherein the single nucleotide polymorphism is associated with a first time from a first symptom of the inflammatory bowel disease to a first surgery, wherein the first time is about four to ten years. (90) The method of embodiment 1, wherein the single nucleotide polymorphism is associated with a second time from a first surgery, wherein the second time is about 2 years months to about 12 years. (91) The method of embodiment 1, wherein the single nucleotide polymorphism is associated with at least one of stricturing and penetrating. (92) The method of embodiment 1, wherein the single nucleotide polymorphism is associated with stricturing. (93) The method of embodiment 1, wherein the single nucleotide polymorphism is associated with isolated penetrating. (94) The method of embodiment 1, wherein the single nucleotide polymorphism is associated with perianal Crohn’s disease. (95) The method of embodiment 1, wherein the single nucleotide polymorphism is associated with pancolitis.

[00331] (96) A kit comprising a set of oligonucleotides for detecting a combination of single nucleotide polymorphisms comprising a risk allele within rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402, rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62l8777l, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs7699929l, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781. (97) The kit of embodiment 96, comprising a microarray chip, wherein the oligonucleotides are probes on the microarray chip. (98) The kit of embodiment 96, wherein the oligonucleotides are primers capable of amplifying portions of at least one nucleic acid encoding GPR35, wherein the portions comprise the combination of single nucleotide polymorphisms. (99) The kit of embodiment 96, comprising a probe for a protein selected from anti-Saccharomyces cerevisiae antibody (ASCA), an anti -neutrophil cytoplasmic antibody (ANCA), and E.coli outer membrane porin protein C (OmpC). (100) The kit of embodiment 96, further comprising an enzyme-linked immunosorbent assay (ELISA), or immunohistochemistry reagent. (101) The kit of embodiment 100, wherein the ELISA comprises fixed neutrophils.

[00332] (102) A method of treating an Inflammatory Bowel Disease (IBD) in a subject, the method comprising administering a therapeutically effective amount of a therapeutic agent that targets GPR35 signaling, provided the subject has an increased or a decreased levels of GPR35 as determined by detecting in a sample obtained from the subject having a single nucleotide polymorphism at a GPR35 locus associated with IBD comprising a risk allele within rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rs!2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a single nucleotide polymorphism in linkage

disequilibrium therewith. (103) The method of embodiment 102, wherein the IBD comprises Crohn’s disease, ulcerative colitis, or perianal Crohn’s disease. (104) The method of embodiment 102, wherein the increased or decreased levels of GPR35 detected in the sample are relative to a level of GPR35 in a control subject without the IBD. (105) The method of embodiment 102, wherein the subject has ulcerative colitis and is predicted to develop pancolitis. (106) The method of embodiment 102, wherein the subject has Crohn’s disease, and wherein the single nucleotide polymorphism is associated with a first time of about four years to about 10 years from a first symptom of the inflammatory bowel disease to a first surgery.

[00333] (107) A method of treating a subject with Crohn’s disease who is predicted to develop perianal Crohn’s disease comprising administering a therapeutically effective therapeutic agent to the subject, provided a single nucleotide polymorphism at a GPR35 locus associated with perianal Crohn’s disease is detected in a sample obtained from the subject, the single nucleotide polymorphism comprising a risk allele within rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl 16803432, rsl3016146, rsl 15661339, rsl 15490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a single nucleotide polymorphism in linkage disequilibrium therewith.

[00334] (108) A method comprising: (a) obtaining a biological sample from a subject; assaying for the presence of at least one single nucleotide polymorphism in a nucleic acid of the biological sample, the single nucleotide polymorphism comprising a risk allele within rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl l6803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a single nucleotide polymorphism in linkage

disequilibrium therewith; and (b) assaying for the presence of a serological marker in a serum or plasma sample, wherein the serological marker comprises ANCA, ASCA, or OmpC. (109) The method of embodiment 108, wherein the biological sample is atissue sample. (110) The method of embodiment 109, wherein the biological sample comprises cells of the gastrointestinal tract. (I l l)

The method of embodiment 109, wherein the biological sample comprises cells of the rectum. (112) The method of embodiment 109, wherein the biological sample comprises cells of the colon. (113)

The method of embodiment 108, wherein assaying comprises use of a genotyping array.

[00335] (114) A method of modifying GPR35 activity or expression in a subject having or suspected of having an inflammatory bowel disease, the method comprising: identifying the subject as being a carrier of a risk allele at a single nucleotide polymorphism within rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl l5684595, rsl l6803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rs l3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a single nucleotide polymorphism in linkage

disequilibrium therewith; and administering to the subject a therapeutically effective amount of a therapeutic agent that modulates GPR35 activity or expression.

[00336] (115) A method of characterizing an inflammatory bowel disease of a subject, the method comprising: assaying genetic material from the subject to identify the presence or absence of a risk allele at a single nucleotide polymorphism within rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl 0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl l6803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a single nucleotide polymorphism in linkage disequilibrium therewith.

[00337] (116) A method of characterizing an inflammatory bowel disease of a subject, the method comprising: assaying genetic material from the subject to identify the presence or absence of a genotype comprising a sequence from SEQ ID NOS: 1-124, or a complement thereof.

[00338] (117) A method for detecting a genotype of interest in a subject comprising an inflammatory bowel disease, the method comprising: (a) contacting genetic material from the subject with a composition sufficiently complementary to and capable of hybridizing to the genotype of interest, the composition comprising: (1) a detectably labeled oligonucleotide probe comprising a sequence provided in SEQ ID NOS: 32-124, or a complement thereof; (2) a detectably labeled oligonucleotide probe comprising a nucleic acid sequence that differs from a probe selected from the group consisting of (i) by up to three nucleobases, provided the detectably labeled oligonucleotide probe of (ii) hybridizes to the genotype of interest, (3) a detectably labeled oligonucleotide probe comprising a nucleic acid sequence complementary to a probe selected from the group consisting of (i)-(ii), or a combination of probes selected from the group consisting of (i)-(ii), and (b) detecting the presence or absence of hybridization of the genetic material with the composition using the detectably labeled oligonucleotide probe, whereby hybridization of the genetic material with the composition is indicative of the presence of the genotype of interest in the subject.

[00339] (118) A composition comprising at least 10 but less than 50 contiguous nucleobase residues of a sequence provided in SEQ ID NOS: 32-124, or its complement, wherein the contiguous nucleobase residues are connected to a detectable molecule. (119) A method comprising contacting DNA from a subject with the composition of embodiment 118 under conditions configured to hybridize the composition to the DNA if the DNA comprises a sequence complementary to the composition. (120) A method comprising treating the subject of embodiment 119 with a modulator of GPR35 activity or expression provided that the DNA from the subject comprises the sequence complementary to the composition.

[00340] (121) A method of treating a patient with a modulator of GPR35 activity or expression, wherein the patient is suffering from an inflammatory bowel disease, the method comprising the steps of:

determining whether the patient has or will develop Crohn’s Disease by: (a) obtaining or having obtained a biological sample from the subject; and (b) performing or having performed a genotyping assay on the biological sample to determine if the subject has a SNP in a GPR35 gene; and if the subject has the SNP, then administering the modulator of GPR35 activity or expression to the patient, and if the subject does not have the SNP, then administering a therapeutic agent other than the modulator of GPR35 activity or expression to the subject. (122) A method of treating a subject with a modulator of GPR35 activity or expression, wherein the subject is suffering from an inflammatory bowel disease, the method comprising the steps of: (a) determining whether the subject has or will develop ulcerative colitis by: obtaining or having obtained a biological sample from the subject; and performing or having performed a genotyping assay on the biological sample to determine if the subject has a SNP in a GPR35 gene; and (b) if the subject has the SNP, then administering the modulator of GPR35 activity or expression to the patient, and if the subject does not have the SNP, then administering a therapeutic agent other than the modulator of GPR35 activity or expression to the subject. (123) A method of treating a patient with a modulator of GPR35 activity or expression, wherein the patient is suffering from an inflammatory bowel disease, the method comprising the steps of: (a) determining whether the patient has or will develop pancolitis by: obtaining or having obtained a biological sample from the subject; and performing or having performed a genotyping assay on the biological sample to determine if the subject has a SNP in a GPR35 gene; and (b) if the subject has the SNP, then administering the modulator of GPR35 activity or expression to the patient, and if the subject does not have the SNP, then administering a therapeutic agent other than the modulator of GPR35 activity or expression to the subject. (124) A method of treating inflammatory bowel disease in a subject comprising administering to the subject a therapeutically effective amount of a modulator of GPR35, provided a SNP is detected in a biological sample obtained from a subject, wherein the SNP is in linkage disequilibrium with rs3749171 as determined by an r² of at least about0.70, about 0.75, about 0.80, about 0.85, about 0.85, about 0.90, or about 1.0. (125) A method of modulating the activity or expression of GPR35 in a subject suffering from an treating inflammatory bowel disease, the method comprising administering to the subject a therapeutically effective amount of a modulator of GPR35, provided a SNP is detected in a biological sample obtained from a subject, wherein the SNP is in linkage disequilibrium with rs3749171 as determined by an r² of at least about0.70, about 0.75, about 0.80, about 0.85, about 0.85, about 0.90, or about 1.0. (126) The method of any one of embodiments 121-126, wherein the SNP comprises rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402, rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743, rs79086701, rs6744241, rsl368222, rs55970834, rsl2477897, rsl2468453, rs72996949, rs62186545, rs754329, rsl0933621, rsl 11471799, rs2975785, rsl 13444107, rs4676403, rs4676404, rs754328, rs2975788, rs2975781, rsl3019955, rs35155396, rs2060188, rs2060189, rsl0933624, rs6760169, rs79222326, rs2975789, rsl2468377, rs75497224, rsl 0804410, rs7556712, rsl 14041303, rs6749767, rsl 15286046, rsl0198255, rs62187771, rsl0203408, rs4676391, rs6753653, rs7587179, rsl0933620, rs6724516, rs6708668, rsl3023028, rsl2622957, rsl2478375, rs4676344, rs2975779, rs6754872, rs4676395, rs4676342, rs6437363, rsl0169210, rs4676345, rs4676337, rsl3385710, rsl3035879, rsl2987037, rs2060190, rs4387788, rs4530367, rs34930434, rs35230312, rs76999291, rs79278957, rs28819809, rs4413160, rs35523523, rsl 15684595, rsl l6803432, rsl3016146, rsl l5661339, rsl l5490519, rs4676394, rs4676392, rsl2474150, rs72996930, rsl0933626, rs35390471, rsl3010070, rs35039554, rsl2999598, rs33978324, rs62187760, rsl2468223, rs62187776, rs62187777, rs62187778, rsl 133726, rsl2468485, rs62187761, rs33986981, rs62187763, rs202172302, rsl3428147, rs74512877, rs75047648, rsl2474648, or rs78571781, or a single nucleotide polymorphism in linkage disequilibrium therewith. (127) The method of any one of embodiments 121-126, wherein the modulator of GPR35 activity or expression is a GPR35 agonist. (128) The method of any one of embodiments 121-126, wherein the modulator of GPR35 activity or expression is a GPR35 antagonist. (129) The method of any one of embodiments 121-126, wherein the modulator of GPR35 activity or expression is a GPR35 binding antibody or antibody fragment. (130) The method of any one of embodiments 121-126, wherein the modulator of GPR35 activity or expression is a GPR35 binding small molecule. (131) The methods of any one of the preceding embodiments, wherein the single nucleotide polymorphism is associated with a risk of a subject developing anti-tumor necrosis factor (TNF) non-response. (132) The method of embodiment 131, wherein the anti-TNF non-response comprises primary non-response or secondary non-response.

[00341] (133) The methods of any one of the preceding embodiments, wherein the single nucleotide polymorphism is associated with a risk of a subject developing arthralgia. (134) The methods of any one of the preceding embodiments, wherein the single nucleotide polymorphism is associated with a risk of a subject developing spondylitis. (135) The methods of any one of the preceding embodiments, wherein the single nucleotide polymorphism is associated with a risk of a subject developing a poor drug metabolism. (136) The methods of any one of the preceding embodiments, wherein the single nucleotide polymorphism is associated with a risk of a subject developing morphological defects in ileal Paneth cells. (137) The method of embodiment 91, wherein the at least one of stricturing and penetrating is isolated to an ileum, ileocolonic region of an intestine, or colon. (138) The method of embodiment 92, wherein the stricturing is isolated to an ileum, ileocolonic region of an intestine, or colon. (139) The method of embodiment 93, wherein the isolated penetrating is isolated to an ileum, ileocolonic, or colon. (140) The methods of any one of the preceding embodiments, wherein the single nucleotide polymorphism is associated with medically refractor ulcerative colitis (mrUC). (141) The method of embodiment 140, wherein the mrUC is characterized by a time to first colectomy that is shorter for a subject expressing the single nucleotide polymorphism as compared to an individual who does not express the single nucleotide

polymorphism. (142) The method of embodiment 140, wherein the mrUC is characterized by a time to second colectomy that is shorter for a subject expressing the single nucleotide polymorphism as compared to an individual who does not express the single nucleotide polymorphism. (143) The method of any one of the preceding embodiments, wherein the single nucleotide polymorphism is associated with an expression of at least one serological marker. (144) The method of embodiment 140, wherein the at least one serological marker comprises anti-Saccharomyces cerevisiae antibody (ASCA), an anti -neutrophil cytoplasmic antibody (ANCA), or E.coli outer membrane porin protein C (OmpC), or a combination thereof.

[00342] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rsl 13435444, (ii)

SEQ ID NO: 1, (iii) SEQ ID NO: 32, (iv) SEQ ID NO: 63, (v) SEQ ID NO: 94, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rsl 13435444, (ii) SEQ ID NO: 1, (iii) SEQ ID NO: 32, (iv) SEQ ID NO: 63, (v) SEQ ID NO: 94, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 32, (ii) SEQ ID NO: 63, (iii) SEQ ID NO: 94, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“G” allele in rsl 13435444. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“G” allele in rsl 13435444, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 32, SEQ ID NO: 63, or SEQ ID NO: 94, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 32, SEQ ID NO: 63, or SEQ ID NO: 94, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rsl 13435444, (ii) SEQ ID NO: 1, (iii) SEQ ID NO: 32, (iv) SEQ ID NO: 63, (v) SEQ ID NO: 94, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rsl 13435444, (ii) SEQ ID NO: 1, (lii) SEQ ID NO: 32, (iv) SEQ ID NO: 63, (v) SEQ ID NO: 94, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00343] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs3749171, (ii) SEQ ID NO: 2, (iii) SEQ ID NO: 33, (iv) SEQ ID NO: 64, (v) SEQ ID NO: 95, (vi) or a combination of (i)- (v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs3749171, (ii) SEQ ID NO: 2, (iii) SEQ ID NO: 33, (iv) SEQ ID NO: 64, (v) SEQ ID NO: 95, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 33, (ii) SEQ ID NO: 64, (iii) SEQ ID NO: 95, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs3749171. (9) The primer pair of embodiment 7 or embodiment 18, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“A” allele in rs3749171, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 33, SEQ ID NO: 64, or SEQ ID NO: 95, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 33, SEQ ID NO: 64, or SEQ ID NO: 95, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises:

(i) rs3749171, (ii) SEQ ID NO: 2, (iii) SEQ ID NO: 33, (iv) SEQ ID NO: 64, (v) SEQ ID NO: 95, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs3749171, (ii) SEQ ID NO: 2, (in) SEQ ID NO: 33, (iv) SEQ ID NO: 64, (v) SEQ ID NO: 95, (vi) or a combination of (i)- (v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00344] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676406, (ii) SEQ ID NO: 3, (iii) SEQ ID NO: 34, (iv) SEQ ID NO: 65, (v) SEQ ID NO: 96, (vi) or a combination of (i)- (v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676406, (ii) SEQ ID NO: 3, (iii) SEQ ID NO: 34, (iv) SEQ ID NO: 65, (v) SEQ ID NO: 96, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 34, (ii) SEQ ID NO: 65, (iii) SEQ ID NO: 96, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs4676406. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs4676406, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 34, SEQ ID NO: 65, or SEQ ID NO: 96, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 34, SEQ ID NO: 65, or SEQ ID NO: 96, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises:

(i) rs4676406, (ii) SEQ ID NO: 3, (iii) SEQ ID NO: 34, (iv) SEQ ID NO: 65, (v) SEQ ID NO: 96, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676406, (ii) SEQ ID NO: 3, (iii) SEQ ID NO: 34, (iv) SEQ ID NO: 65, (v) SEQ ID NO: 96, (vi) or a combination of (i)- (v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00345] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676399, (ii) SEQ ID NO: 4, (hi) SEQ ID NO: 35, (iv) SEQ ID NO: 66, (v) SEQ ID NO: 97, (vi) or a combination of (i)- (v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676399, (ii) SEQ ID NO: 4, (iii) SEQ ID NO: 35, (iv) SEQ ID NO: 66, (v) SEQ ID NO: 97, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 35, (ii) SEQ ID NO: 66, (iii) SEQ ID NO: 97, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“C” allele in rs4676399. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “C” allele in rs4676399, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 35, SEQ ID NO: 66, or SEQ ID NO: 97, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 35, SEQ ID NO: 66, or SEQ ID NO: 97, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises:

(i) rs4676399, (ii) SEQ ID NO: 4, (hi) SEQ ID NO: 36, (iv) SEQ ID NO: 66, (v) SEQ ID NO: 97, (vi) or a combination of (i)-(v). (14) The method of embodiment 13 wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676399, (ii) SEQ ID NO: 4, (iii) SEQ ID NO: 35, (iv) SEQ ID NO: 66, (v) SEQ ID NO: 97, (vi) or a combination of (i)- (v). (16) The method of any one of embodiments 13-16, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 15-18, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00346] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs2975782, (ii) SEQ ID NO: 5, (iii) SEQ ID NO: 36, (iv) SEQ ID NO: 67, (v) SEQ ID NO: 98, (vi) or a combination of (i)- (v), and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2975782, (ii) SEQ ID NO: 5, (hi) SEQ ID NO: 36, (iv) SEQ ID NO: 67, (v) SEQ ID NO: 98, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 36, (ii) SEQ ID NO: 67, (iii) SEQ ID NO: 98, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs2975782. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs2975782, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 36, SEQ ID NO: 67, or SEQ ID NO: 98, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 36, SEQ ID NO: 67, or SEQ ID NO: 98, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises:

(i) rs2975782, (ii) SEQ ID NO: 5, (iii) SEQ ID NO: 36, (iv) SEQ ID NO: 67, (v) SEQ ID NO: 98, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2975782, (ii) SEQ ID NO: 5, (iii) SEQ ID NO: 36, (iv) SEQ ID NO: 67, (v) SEQ ID NO: 98, (vi) or a combination of (i)- (v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

[00347] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs3749172, (ii) SEQ ID NO: 6, (iii) SEQ ID NO: 37, (iv) SEQ ID NO: 68, (v) SEQ ID NO: 99, (vi) or a combination of (i)- (v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-4, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-5, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs3749172, (ii) SEQ ID NO: 6, (iii) SEQ ID NO: 37, (in) SEQ ID NO: 68, (v) SEQ ID NO: 99, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 37, (ii) SEQ ID NO: 68, (iii) SEQ ID NO: 99, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“C” allele in rs3749172. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “C” allele in rs3749172, and wherein the probe comprises a detectable label. (11) A nucleic acid probe compnsing SEQ ID NO: 37, SEQ ID NO: 68, or SEQ ID NO: 99, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 37, SEQ ID NO: 68, or SEQ ID NO: 99, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises:

(i) rs3749172, (ii) SEQ ID NO: 6, (iii) SEQ ID NO: 37, (iv) SEQ ID NO: 68, (v) SEQ ID NO: 99, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs3749172, (ii) SEQ ID NO: 6, (iii) SEQ ID NO: 37, (iv) SEQ ID NO: 68, (v) SEQ ID NO: 99, (vi) or a combination of (i)- (v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

[00348] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs79844648, (ii) SEQ ID NO: 7, (iii) SEQ ID NO: 38, (iv) SEQ ID NO: 69, (v) SEQ ID NO: 100, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs79844648, (ii) SEQ ID NO: 7, (iii) SEQ ID NO: 38, (iv) SEQ ID NO: 69, (v) SEQ ID NO: 100, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 38, (ii) SEQ ID NO: 69, (iii) SEQ ID NO: 100, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“G” allele in rs79844648. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“G” allele in rs79844648, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 38, SEQ ID NO: 69, or SEQ ID NO: 100, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 38, SEQ ID NO: 69, or SEQ ID NO: 100, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs79844648, (ii) SEQ ID NO: 7, (iii) SEQ ID NO: 38, (iv) SEQ ID NO: 69, (v) SEQ ID NO: 100, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs79844648, (ii) SEQ ID NO: 7, (iii) SEQ ID NO: 38, (iv) SEQ ID NO: 69, (v) SEQ ID NO: 100, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00349] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676402, (ii) SEQ ID NO: 8, (iii) SEQ ID NO: 39, (iv) SEQ ID NO: 70, (v) SEQ ID NO: 101, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676402, (ii) SEQ ID NO: 8, (iii) SEQ ID NO: 39, (IV) SEQ ID NO: 70, (v) SEQ ID NO: 101, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 39, (ii) SEQ ID NO: 70, (iii) SEQ ID NO: 101, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs4676402. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs4676402, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 39, SEQ ID NO: 70, or SEQ ID NO: 101, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 39, SEQ ID NO: 70, or SEQ ID NO: 101, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs4676402, (ii) SEQ ID NO: 8, (iii) SEQ ID NO: 39, (iv) SEQ ID NO: 70, (v) SEQ ID NO: 101, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676402, (ii) SEQ ID NO: 8, (iii) SEQ ID NO: 39, (iv) SEQ ID NO: 70, (v) SEQ ID NO: 101, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00350] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs2975780, (ii) SEQ ID NO: 9, (hi) SEQ ID NO: 40, (iv) SEQ ID NO: 71, (v) SEQ ID NO: 102, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2975780, (ii) SEQ ID NO: 9, (iii) SEQ ID NO: 40, (iv) SEQ ID NO: 71, (v) SEQ ID NO: 102, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 40, (ii) SEQ ID NO: 71, (iii) SEQ ID NO: 102, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs2975780. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs2975780, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 40, SEQ ID NO: 71, or SEQ ID NO: 102, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 40, SEQ ID NO: 71, or SEQ ID NO: 102, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs2975780, (ii) SEQ ID NO: 9, (iii) SEQ ID NO: 40, (iv) SEQ ID NO: 71, (v) SEQ ID NO: 102, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2975780, (ii) SEQ ID NO: 9, (iii) SEQ ID NO: 40, (iv) SEQ ID NO: 71, (v) SEQ ID NO: 102, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00351] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676396, (ii) SEQ ID NO: 10, (iii) SEQ ID NO: 41, (IV) SEQ ID NO: 72, (v) SEQ ID NO: 103, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676396, (ii) SEQ ID NO: 10, (hi) SEQ ID NO: 41, (iv) SEQ ID NO: 72, (v) SEQ ID NO: 103, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 41, (ii) SEQ ID NO: 72, (iii) SEQ ID NO: 103, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs4676396. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs4676396, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 41, SEQ ID NO: 72, or SEQ ID NO: 103, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 41, SEQ ID NO: 72, or SEQ ID NO: 103, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs4676396, (ii) SEQ ID NO: 10, (iii) SEQ ID NO: 41, (iv) SEQ ID NO: 72, (v) SEQ ID NO: 103, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676396, (ii) SEQ ID NO: 10, (iii) SEQ ID NO: 41, (iv) SEQ ID NO: 72, (v) SEQ ID NO: 103, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00352] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs6735672, (ii) SEQ ID NO: 11, (iii) SEQ ID NO: 42, (iv) SEQ ID NO: 73, (v) SEQ ID NO: 104, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6735672, (ii) SEQ ID NO: 11, (hi) SEQ ID NO: 42, (iv) SEQ ID NO: 73, (v) SEQ ID NO: 104, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 42, (ii) SEQ ID NO: 73, (iii) SEQ ID NO: 104, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs6735672. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs6735672, and wherein the probe comprises a detectable label. (11) A nucleic acid probe compnsing SEQ ID NO: 42, SEQ ID NO: 73, or SEQ ID NO: 104, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 42, SEQ ID NO: 73, or SEQ ID NO: 104, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs6735672, (ii) SEQ ID NO: 11, (iii) SEQ ID NO: 42, (iv) SEQ ID NO: 73, (v) SEQ ID NO: 104, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6735672, (ii) SEQ ID NO: 11, (iii) SEQ ID NO: 42, (iv) SEQ ID NO: 73, (v) SEQ ID NO: 104, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00353] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs34228697, (ii) SEQ ID NO: 12, (lii) SEQ ID NO: 43, (IV) SEQ ID NO: 74, (v) SEQ ID NO: 105, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs34228697, (ii) SEQ ID NO: 12, (iii) SEQ ID NO: 43, (iv) SEQ ID NO: 74, (v) SEQ ID NO: 105, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 43, (ii) SEQ ID NO: 74, (iii) SEQ ID NO: 105, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs34228697. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“A” allele in rs34228697, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 43, SEQ ID NO: 74, or SEQ ID NO: 105, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 43, SEQ ID NO: 74, or SEQ ID NO: 105, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs34228697, (ii) SEQ ID NO: 12, (iii) SEQ ID NO: 43, (iv) SEQ ID NO: 74, (v) SEQ ID NO: 105, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs34228697, (ii) SEQ ID NO: 12, (iii) SEQ ID NO: 43, (iv) SEQ ID NO: 74, (v) SEQ ID NO: 105, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclimcal phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00354] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676401, (ii) SEQ ID NO: 13, (iii) SEQ ID NO: 44, (iv) SEQ ID NO: 75, (v) SEQ ID NO: 106, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676401, (ii) SEQ ID NO: 13, (hi) SEQ ID NO: 44, (iv) SEQ ID NO: 75, (v) SEQ ID NO: 106, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 44, (ii) SEQ ID NO: 75, (iii) SEQ ID NO: 106, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs4676401. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs4676401, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 44, SEQ ID NO: 75, or SEQ ID NO: 106, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 44, SEQ ID NO: 75, or SEQ ID NO: 106, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs4676401, (ii) SEQ ID NO: 13, (iii) SEQ ID NO: 44, (iv) SEQ ID NO: 75, (v) SEQ ID NO: 106, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676401, (ii) SEQ ID NO: 13, (iii) SEQ ID NO: 44, (iv) SEQ ID NO: 75, (v) SEQ ID NO: 106, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00355] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs2975786, (ii) SEQ ID NO: 14, (hi) SEQ ID NO: 45, (iv) SEQ ID NO: 76, (v) SEQ ID NO: 107, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, admimstenng to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2975786, (ii) SEQ ID NO: 14, (iii) SEQ ID NO: 45, (iv) SEQ ID NO: 76, (v) SEQ ID NO: 107, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 45, (ii) SEQ ID NO: 76, (iii) SEQ ID NO: 107, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“G” allele in rs2975786. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “G” allele in rs2975786, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 45, SEQ ID NO: 76, or SEQ ID NO: 107, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 45, SEQ ID NO: 76, or SEQ ID NO: 107, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs2975786, (ii) SEQ ID NO: 14, (hi) SEQ ID NO: 45, (iv) SEQ ID NO: 76, (v) SEQ ID NO: 107, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2975786, (ii) SEQ ID NO: 14, (iii) SEQ ID NO: 45, (iv) SEQ ID NO: 76, (v) SEQ ID NO: 107, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00356] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676346, (ii) SEQ ID NO: 15, (lii) SEQ ID NO: 46, (IV) SEQ ID NO: 77, (v) SEQ ID NO: 108, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676346, (ii) SEQ ID NO: 15, (hi) SEQ ID NO: 46, (iv) SEQ ID NO: 77, (v) SEQ ID NO: 108, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 46, (ii) SEQ ID NO: 77, (iii) SEQ ID NO: 108, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs4676346. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs4676346, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 46, SEQ ID NO: 77, or SEQ ID NO: 108, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 46, SEQ ID NO: 77, or SEQ ID NO: 108, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs4676346, (ii) SEQ ID NO: 15, (hi) SEQ ID NO: 46, (iv) SEQ ID NO: 77, (v) SEQ ID NO: 108, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676346, (ii) SEQ ID NO: 15, (iii) SEQ ID NO: 46, (iv) SEQ ID NO: 77, (v) SEQ ID NO: 108, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00357] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs6437356, (ii) SEQ ID NO: 16, (iii) SEQ ID NO: 47, (iv) SEQ ID NO: 78, (v) SEQ ID NO: 109, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6437356, (ii) SEQ ID NO: 16, (iii) SEQ ID NO: 47, (iv) SEQ ID NO: 78, (v) SEQ ID NO: 109, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 47, (ii) SEQ ID NO: 78, (iii) SEQ ID NO: 109, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs6437356. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs6437356, and wherein the probe comprises a detectable label. (11) A nucleic acid probe compnsing SEQ ID NO: 47, SEQ ID NO: 78, or SEQ ID NO: 109, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 47, SEQ ID NO: 78, or SEQ ID NO: 109, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs6437356, (ii) SEQ ID NO: 16, (iii) SEQ ID NO: 47, (iv) SEQ ID NO: 78, (v) SEQ ID NO: 109, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6437356, (ii) SEQ ID NO: 16, (iii) SEQ ID NO: 47, (iv) SEQ ID NO: 78, (v) SEQ ID NO: 109, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00358] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs6745185, (ii) SEQ ID NO: 17, (lii) SEQ ID NO: 48, (IV) SEQ ID NO: 79, (v) SEQ ID NO: 110, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6745185, (ii) SEQ ID NO: 17, (iii) SEQ ID NO: 48, (iv) SEQ ID NO: 79, (v) SEQ ID NO: 110, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 48, (ii) SEQ ID NO: 79, (iii) SEQ ID NO: 110, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“C” allele in rs6745185. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “C” allele in rs6745185, and wherein the probe comprises a detectable label (11) A nucleic acid probe comprising SEQ ID NO: 48, SEQ ID NO: 79, or SEQ ID NO: 110, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 48, SEQ ID NO: 79, or SEQ ID NO: 110, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs6745185, (ii) SEQ ID NO: 17, (hi) SEQ ID NO: 48, (iv) SEQ ID NO: 79, (v) SEQ ID NO: 110, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6745185, (ii) SEQ ID NO: 17, (m) SEQ ID NO: 48, (iv) SEQ ID NO: 79, (v) SEQ ID NO: 110, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclimcal phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00359] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676407, (ii) SEQ ID NO: 18, (iii) SEQ ID NO: 49, (iv) SEQ ID NO: 80, (v) SEQ ID NO: 111, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676407, (ii) SEQ ID NO: 18, (iii) SEQ ID NO: 49, (iv) SEQ ID NO: 80, (v) SEQ ID NO: 111, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 49, (ii) SEQ ID NO: 80, (iii) SEQ ID NO: 111, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“G” allele in rs4676407. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “G” allele in rs4676407, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 49, SEQ ID NO: 80, or SEQ ID NO: 111, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 49, SEQ ID NO: 80, or SEQ ID NO: 111, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs4676407, (ii) SEQ ID NO: 18, (iii) SEQ ID NO: 49, (iv) SEQ ID NO: 80, (v) SEQ ID NO: 111, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676407, (ii) SEQ ID NO: 18, (iii) SEQ ID NO: 49, (iv) SEQ ID NO: 80, (v) SEQ ID NO: 111 , (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00360] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs2953156, (ii) SEQ ID NO: 19, (hi) SEQ ID NO: 50, (iv) SEQ ID NO: 81, (v) SEQ ID NO: 112, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2953156, (ii) SEQ ID NO: 19, (iii) SEQ ID NO: 50, (iv) SEQ ID NO: 81, (v) SEQ ID NO: 112, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 50, (ii) SEQ ID NO: 81, (iii) SEQ ID NO: 112, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“G” allele in rs2953156. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “G” allele in rs2953156, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 50, SEQ ID NO: 81, or SEQ ID NO: 112, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 50, SEQ ID NO: 81, or SEQ ID NO: 112, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises : (i) rs2953156, (ii) SEQ ID NO : 19, (hi) SEQ ID NO : 50, (iv) SEQ ID NO : 81 , (v) SEQ ID NO: 112, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2953156, (ii) SEQ ID NO: 19, (iii) SEQ ID NO: 50, (iv) SEQ ID NO: 81, (v) SEQ ID NO: 112, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00361] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4335944, (ii) SEQ ID NO: 20, (lii) SEQ ID NO: 51, (IV) SEQ ID NO: 82, (v) SEQ ID NO: 113, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4335944, (ii) SEQ ID NO: 20, (ill) SEQ ID NO: 51, (iv) SEQ ID NO: 82, (v) SEQ ID NO: 113, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 51, (ii) SEQ ID NO: 82, (iii) SEQ ID NO: 113, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“C” allele in rs4335944. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “C” allele in rs4335944, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 51, SEQ ID NO: 82, or SEQ ID NO: 113, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 51, SEQ ID NO: 82, or SEQ ID NO: 113, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs4335944, (ii) SEQ ID NO: 20, (iii) SEQ ID NO: 51, (iv) SEQ ID NO: 82, (v) SEQ ID NO: 113, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4335944, (ii) SEQ ID NO: 20, (iii) SEQ ID NO: 51, (iv) SEQ ID NO: 82, (v) SEQ ID NO: 113, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00362] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs73999973, (ii) SEQ ID NO: 21, (iii) SEQ ID NO: 52, (iv) SEQ ID NO: 83, (v) SEQ ID NO: 114, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs73999973, (ii) SEQ ID NO: 21, (iii) SEQ ID NO: 52, (iv) SEQ ID NO: 83, (v) SEQ ID NO: 114, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 52, (ii) SEQ ID NO: 83, (iii) SEQ ID NO: 114, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs73999973. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“A” allele in rs73999973, and wherein the probe comprises a detectable label. (11) A nucleic acid probe compnsing SEQ ID NO: 52, SEQ ID NO: 83, or SEQ ID NO: 114, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 52, SEQ ID NO: 83, or SEQ ID NO: 114, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs73999973, (ii) SEQ ID NO: 21, (iii) SEQ ID NO: 52, (iv) SEQ ID NO: 83, (v) SEQ ID NO: 114, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs73999973, (ii) SEQ ID NO: 21, (iii) SEQ ID NO: 52, (iv) SEQ ID NO: 83, (v) SEQ ID NO: 114, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00363] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676410, (ii) SEQ ID NO: 22, (lii) SEQ ID NO: 53, (IV) SEQ ID NO: 84, (v) SEQ ID NO: 115, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676410, (ii) SEQ ID NO: 22, (iii) SEQ ID NO: 53, (iv) SEQ ID NO: 84, (v) SEQ ID NO: 115, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 53, (ii) SEQ ID NO: 84, (iii) SEQ ID NO: 115, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs4676410. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs4676410, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 53, SEQ ID NO: 84, or SEQ ID NO: 115, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 53, SEQ ID NO: 84, or SEQ ID NO: 115, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs4676410, (ii) SEQ ID NO: 22, (hi) SEQ ID NO: 53, (iv) SEQ ID NO: 84, (v) SEQ ID NO: 115, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybndizes to (i) rs4676410, (ii) SEQ ID NO: 22, (m) SEQ ID NO: 53, (iv) SEQ ID NO: 84, (v) SEQ ID NO: 115, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclimcal phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00364] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs4676405, (ii) SEQ ID NO: 23, (iii) SEQ ID NO: 54, (iv) SEQ ID NO: 85, (v) SEQ ID NO: 116, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676405, (ii) SEQ ID NO: 23, (iii) SEQ ID NO: 54, (iv) SEQ ID NO: 85, (v) SEQ ID NO: 116, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 54, (ii) SEQ ID NO: 85, (iii) SEQ ID NO: 116, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“G” allele in rs4676405. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “G” allele in rs4676405, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 54, SEQ ID NO: 85, or SEQ ID NO: 116, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 54, SEQ ID NO: 85, or SEQ ID NO: 116, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs4676405, (ii) SEQ ID NO: 23, (iii) SEQ ID NO: 54, (iv) SEQ ID NO: 85, (v) SEQ ID NO: 116, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs4676405, (ii) SEQ ID NO: 23, (iii) SEQ ID NO: 54, (iv) SEQ ID NO: 85, (v) SEQ ID NO: 116, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00365] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs2953154, (ii) SEQ ID NO: 24, (hi) SEQ ID NO: 55, (iv) SEQ ID NO: 86, (v) SEQ ID NO: 117, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2953154, (ii) SEQ ID NO: 24, (iii) SEQ ID NO: 55, (iv) SEQ ID NO: 86, (v) SEQ ID NO: 117, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 55, (ii) SEQ ID NO: 86, (iii) SEQ ID NO: 117, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“G” allele in rs2953154. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “G” allele in rs2953154, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 55, SEQ ID NO: 86, or SEQ ID NO: 117, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 55, SEQ ID NO: 86, or SEQ ID NO: 117, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs2953154, (ii) SEQ ID NO: 24, (hi) SEQ ID NO: 55, (iv) SEQ ID NO: 86, (v) SEQ ID NO: 117, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs2953154, (ii) SEQ ID NO: 24, (iii) SEQ ID NO: 55, (iv) SEQ ID NO: 86, (v) SEQ ID NO: 117, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00366] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs6732874, (ii) SEQ ID NO: 25, (lii) SEQ ID NO: 56, (IV) SEQ ID NO: 87, (v) SEQ ID NO: 118, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6732874, (ii) SEQ ID NO: 25, (hi) SEQ ID NO: 56, (iv) SEQ ID NO: 87, (v) SEQ ID NO: 118, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 56, (ii) SEQ ID NO: 87, (iii) SEQ ID NO: 118, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs6732874. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs6732874, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 56, SEQ ID NO: 87, or SEQ ID NO: 118, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 56, SEQ ID NO: 87, or SEQ ID NO: 118, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs6732874, (ii) SEQ ID NO: 25, (hi) SEQ ID NO: 56, (iv) SEQ ID NO: 87, (v) SEQ ID NO: 118, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6732874, (ii) SEQ ID NO: 25, (iii) SEQ ID NO: 56, (iv) SEQ ID NO: 87, (v) SEQ ID NO: 118, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00367] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs55862430, (ii) SEQ ID NO: 26, (iii) SEQ ID NO: 57, (iv) SEQ ID NO: 88, (v) SEQ ID NO: 119, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs55862430, (ii) SEQ ID NO: 26, (iii) SEQ ID NO: 57, (iv) SEQ ID NO: 88, (v) SEQ ID NO: 119, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to atarget nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 57, (ii) SEQ ID NO: 88, (iii) SEQ ID NO: 119, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“G” allele in rs55862430. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“G” allele in rs55862430, and wherein the probe comprises a detectable label. (11) A nucleic acid probe compnsing SEQ ID NO: 57, SEQ ID NO: 88, or SEQ ID NO: 119, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 57, SEQ ID NO: 88, or SEQ ID NO: 119, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs55862430, (ii) SEQ ID NO: 26, (iii) SEQ ID NO: 57, (iv) SEQ ID NO: 88, (v) SEQ ID NO: 119, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs55862430, (ii) SEQ ID NO: 26, (iii) SEQ ID NO: 57, (iv) SEQ ID NO: 88, (v) SEQ ID NO: 119, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00368] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rsl2621598, (ii) SEQ ID NO: 27, (lii) SEQ ID NO: 58, (IV) SEQ ID NO: 89, (v) SEQ ID NO: 120, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rsl2621598, (ii) SEQ ID NO: 27, (iii) SEQ ID NO: 58, (iv) SEQ ID NO: 89, (v) SEQ ID NO: 120, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 58, (ii) SEQ ID NO: 89, (iii) SEQ ID NO: 120, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rsl2621598. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“A” allele in rsl2621598, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 58, SEQ ID NO: 89, or SEQ ID NO: 120, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 58, SEQ ID NO: 89, or SEQ ID NO: 120, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs 12621598, (ii) SEQ ID NO: 27, (iii) SEQ ID NO: 58, (iv) SEQ ID NO: 89, (v) SEQ ID NO: 120, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rsl262l598, (ii) SEQ ID NO: 27, (iii) SEQ ID NO: 58, (iv) SEQ ID NO: 89, (v) SEQ ID NO: 120, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclimcal phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00369] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs55919442, (ii) SEQ ID NO: 28, (iii) SEQ ID NO: 59, (iv) SEQ ID NO: 90, (v) SEQ ID NO: 121, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs55919442, (ii) SEQ ID NO: 28, (iii) SEQ ID NO: 59, (iv) SEQ ID NO: 90, (v) SEQ ID NO: 121, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 59, (ii) SEQ ID NO: 90, (iii) SEQ ID NO: 121, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs55919442. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“A” allele in rs55919442, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 59, SEQ ID NO: 190, or SEQ ID NO: 121, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 59, SEQ ID NO: 90, or SEQ ID NO: 121, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs55919442, (h) SEQ ID NO: 28, (iii) SEQ ID NO: 59, (iv) SEQ ID NO: 90, (v) SEQ ID NO: 121, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs55919442, (ii) SEQ ID NO: 28, (lii) SEQ ID NO: 59, (iv) SEQ ID NO: 90, (v) SEQ ID NO: 121 , (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00370] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs74991608, (ii) SEQ ID NO: 29, (hi) SEQ ID NO: 60, (iv) SEQ ID NO: 91, (v) SEQ ID NO: 122, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs74991608, (ii) SEQ ID NO: 29, (iii) SEQ ID NO: 60, (iv) SEQ ID NO: 91, (v) SEQ ID NO: 122, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 60, (ii) SEQ ID NO: 91, (iii) SEQ ID NO: 122, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs74991608. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the“A” allele in rs74991608, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 60, SEQ ID NO: 91, or SEQ ID NO: 122, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 60, SEQ ID NO: 91, or SEQ ID NO: 122, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs74991608, (ii) SEQ ID NO: 29, (hi) SEQ ID NO: 60, (iv) SEQ ID NO: 91, (v) SEQ ID NO: 122, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs74991608, (ii) SEQ ID NO: 29, (iii) SEQ ID NO: 60, (iv) SEQ ID NO: 91, (v) SEQ ID NO: 122, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00371] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs34826997, (ii) SEQ ID NO: 30, (lii) SEQ ID NO: 61, (IV) SEQ ID NO: 92, (v) SEQ ID NO: 123, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD,

CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs34826997, (h) SEQ ID NO: 30, (hi) SEQ ID NO: 61, (iv) SEQ ID NO: 92, (v) SEQ ID NO: 123, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid

amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 61, (ii) SEQ ID NO: 92, (iii) SEQ ID NO: 123, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“T” allele in rs34826997. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “T” allele in rs34826997, and wherein the probe comprises a detectable label. (11) A nucleic acid probe comprising SEQ ID NO: 61, SEQ ID NO: 92, or SEQ ID NO: 123, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 61, SEQ ID NO: 92, or SEQ ID NO: 123, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs34826997, (ii) SEQ ID NO: 30, (iii) SEQ ID NO: 61, (iv) SEQ ID NO: 92, (v) SEQ ID NO: 123, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs34826997, (ii) SEQ ID NO: 30, (iii) SEQ ID NO: 61, (iv) SEQ ID NO: 92, (v) SEQ ID NO: 123, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location ( e.g ., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00372] (1) A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rs6437364, (ii) SEQ ID NO: 31, (iii) SEQ ID NO: 62, (iv) SEQ ID NO: 93, (v) SEQ ID NO: 124, (vi) or a combination of (i)-(v); and if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression. (2) The method of embodiment 1, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (3) The method of embodiment 1 or 2, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (4) The method of any one of embodiments 1-3, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI. (5) The method of any one of embodiments 1-4, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject. (6) The method of embodiment 5, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6437364, (ii) SEQ ID NO: 31, (iii) SEQ ID NO: 62, (iv) SEQ ID NO: 93, (v) SEQ ID NO: 124, (vi) or a combination of (i)-(v). (7) A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises (i) SEQ ID NO: 62, (ii) SEQ ID NO: 93, (iii) SEQ ID NO: 124, or (iv) a combination of (i)-(iii), and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label. (8) The primer pair of embodiment 7, wherein the nucleotide variance comprises a“A” allele in rs6437364. (9) The primer pair of embodiment 7 or embodiment 8, wherein the nucleic acid amplification assay comprises polymerase chain reaction. (10) A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises the “A” allele in rs6437364, and wherein the probe comprises a detectable label. (11) A nucleic acid probe compnsing SEQ ID NO: 62, SEQ ID NO: 93, or SEQ ID NO: 124, and a detectable label. (12) A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of SEQ ID NO: 62, SEQ ID NO: 93, or SEQ ID NO: 124, and a detectable label. (13) A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulatory of GPR35; wherein the GPR35 genotype comprises: (i) rs6437364, (ii) SEQ ID NO: 31, (iii) SEQ ID NO: 62, (iv) SEQ ID NO: 93, (v) SEQ ID NO: 124, (vi) or a combination of (i)-(v). (14) The method of embodiment 13, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject. (15) The method of embodiment 14, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rs6437364, (ii) SEQ ID NO: 31, (iii) SEQ ID NO: 62, (iv) SEQ ID NO: 93, (v) SEQ ID NO: 124, (vi) or a combination of (i)-(v). (16) The method of any one of embodiments 13-15, wherein the inflammatory disease or condition is IBD, CD, UC, or a condition indicative of developing a subclinical phenotype of IBD, CD, or UC. For example, the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof. (17) The method of any one of embodiments 13-16, wherein the modulator of GPR35 activity or expression is an activator of GPR35. (18) The method of any one of embodiments 13-17, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

[00373] While embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

Table 30. Sequence Listing

Claims

CLAIMS What is claimed is

1. A method of treating a subject having an inflammatory disease or condition, the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124; and (b) if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression.

2. A method of treating a subject having an inflammatory disease or condition, the method comprising: administering to the subject a modulator of GPR35 activity or expression, provided a biological sample from the subject has been determined to comprise a GPR35 genotype, wherein the GPR35 genotype comprises a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124.

3. The method of claim 1 or claim 2, wherein the inflammatory disease or condition comprises inflammatory bowel disease (IBD).

4. The method of claim 1 or claim 2, wherein the inflammatory disease or condition comprises a condition indicative of developing a subclinical phenotype of inflammatory bowel disease.

5. The method of claim 4, wherein the subclinical phenotype comprises at least one of

stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location, perianal CD, medically refractory UC, pancolitis, arthralgia, and spondylitis (Bechterew’s disease).

6. The method of claim 5, wherein the disease location comprises at least one of ileum, colon, ileocolonic, upper GI, and rectum.

7. The method of any one of claims 1-6, wherein the modulator of GPR35 activity or expression is an activator of GPR35.

8. The method of any one of claims 1 -7, wherein the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.

9. The method of any one of claims 1-8, wherein determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject.

10. The method of claim 9, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to a sequence selected from SEQ ID NOS: 63-124.

11. A primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the target nucleic acid comprises a sequence selected from SEQ ID NOS: 63-124; and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label.

12. The primer pair of claim 11, wherein the nucleotide variance comprises: (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an“A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs4676401, (xiv) a“G” allele in rs2975786, (xv) an“A” allele in rs4676346, (xvi) an“A” allele in rs6437356, (xvii) a“C” allele in rs6745185, (xviii) a“G” allele in rs4676407, (xix) a“G” allele in rs2953156, (xx) a“C” allele in rs4335944, (xxi) an“A” allele in rs73999973, (xxii) an“A” allele in rs4676410, (xxiii) a“G” allele in rs4676405, (xxiv) a “G” allele in rs2953154, (xxv) an“A” allele in rs6732874, (xxvi) a“G” allele in rs55862430, (xxvii) an“A” allele in rs 12621598, (xxviii) an“A” allele in rs55919442, (xxix) an“A” allele in rs74991608, or (xxx) a“T” allele in rs34826997.

13. The primer pair of claim 11 or claim 12, wherein the nucleic acid amplification assay

comprises polymerase chain reaction.

14. A nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises: (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an“A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an “A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs4676401, (xiv) a“G” allele in rs2975786, (xv) an“A” allele in rs4676346, (xvi) an“A” allele in rs6437356, (xvii) a“C” allele in rs6745185, (xviii) a“G” allele in rs4676407, (xix) a“G” allele in rs2953156, (xx) a“C” allele in rs4335944, (xxi) an“A” allele in rs73999973, (xxii) an“A” allele in rs4676410, (xxiii) a“G” allele in rs4676405, (xxiv) a“G” allele in rs2953154, (xxv) an“A” allele in rs6732874, (xxvi) a“G” allele in rs55862430, (xxvii) an “A” allele in rsl2621598, (xxviii) an“A” allele in rs55919442, (xxix) an“A” allele in rs74991608, or (xxx) a“T” allele in rs34826997; and wherein the probe comprises a detectable label.

15. A nucleic acid probe comprising a sequence selected from SEQ ID NOS: 32-124, and a detectable label.

16. A nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of a sequence selected from SEQ ID NOS: 32-124, and a detectable label.

17. A method for treating a subject having an inflammatory disease or condition, the method comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulator of GPR35; wherein the GPR35 genotype comprises a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124

18. The method of claim 17, wherein the determining comprises performing or having performed a genotyping assay on the biological sample from the subject.

19. The method of claim 18, wherein the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to a sequence selected from SEQ ID NOS: 63-124.

20. The method of any one of claims 17-19, wherein the inflammatory disease or condition comprises inflammatory bowel disease (IBD).

21. The method of any one of claims 17-20, wherein the inflammatory disease or condition comprises a condition indicative of developing a subclinical phenotype of inflammatory bowel disease.

22. The method of claim 21, wherein the subclinical phenotype comprises at least one of

23. The method of claim 22, wherein the disease location comprises at least one of ileum, colon, ileocolonic, upper GI, and rectum.

24. The method of any one of claims 17-23, wherein the modulator of GPR35 activity or

expression is an activator of GPR35.

25. The method of any one of claims 17-24, wherein the modulator of GPR35 activity or

expression comprises a compound selected from Formulas I-XXVI.

26. Use of a compound selected from Formulas I-XXYI to treat a subject determined to comprise a condition indicative of developing an inflammatory bowel disease subclinical phenotype, wherein the subclinical phenotype comprises one or more of stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location, perianal CD, medically refractory UC, pancolitis, arthralgia, and spondylitis (Bechterew’s disease).

27. Use of a compound selected from Formulas I-XXYI to treat a subject comprising a GPR35 genotype comprising a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124.