CA2547824A1 - Assessment of risk for colorectal cancer - Google Patents

Abstract

Disclosed is a method for identifying an individual who has an altered risk for developing colorectal cancer comprising detecting a single nucleotide polymorphism (SNP).

Description

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ASSESSMENT OF RISK FOR COLORECTAL CANCER
FIELD OF THE INVENTION
This invention relates to prediction of the susceptibility of an individual to colorectal cancer. Basis for the prediction lies in relating an individual's genetic makeup, as through molecular analysis, to the genetic makeup of a population of individuals.
BACKGROUND
During the course of evolution, spontaneous mutations arise in the genomes of organisms. Variations in genomic DNA sequences are created continuously at a rate of about 100 new base changes per individual (Kondrashov, 1995; Crow, 1995). These germ-line changes may produce an evolutionary advantage and be retained in the population, or they may be deleterious and ultimately eliminated. In many cases, equilibrium between multiple germline forms of a sequence is established within a population if reproductive ability of individuals containing either polymorphism is not affected. Over time, significant numbers of mutations have accumulated within the human population that may be observed to varying extents in geographically separated groups based upon the presence of common ancestors.

Colorectal cancer is the third most common cancer and the third most common cause of death from cancer for both men and women. Colorectal cancer is responsible for more deaths that are not due primarily to tobacco use than any other type of cancer and inflicts a huge financial burden. Early detection of some human tumors such as uterine cervical cancer has dramatically reduced mortality from this condition (Herzog, 2003). Early detection of colorectal cancer can reasonably be expected to prevent death from this condition by identifying patients at risk for the disease, or those with the disease in an early stage and allow life saving intervention. A validated genetic test for colon cancer predisposition will have clinical utility, allowing prevention of cancer mortality through targeted screening programs. There are good reasons to expect that at least some of the genetic risks of common disease is due to common variants - for example, based on evolutionary arguments, and the fact that most human genetic variation is common. Although approximately 20% of colorectal cancers have a familial component with relatives exhibiting a doubling of risk (Carstensen et al., 1996), less than 5%
of colorectal cancer is explained by rare, highly penetrant genetic syndromes such as APC and HNPCC
(de Leon et al., 1999). Familial colon cancer occurring in patterns inconsistent with classical inherited syndromes suggests that variation in genome sequence plays a major role in determining individual risk to colon cancer. These genetic causes appear complex due to a variety of reasons such as genetic heterogeneity, incomplete penetrance, phenocopies and variation in exposures to environmental co-factors etc. There is little insight into the genetic or environmental determinants of almost 90% of cases of human colorectal carcinoma (Lynch and de La, 2003).

Although common human genetic variation is limited compared to other species, it remains impractical to discover and test every one of the estimated 10,000,000 common genotype variants (Sachidanandam et al., 2001) as predictors of disease risk. Genotypic complexity is reduced through linkage disequilibrium that exists across long segments of the human genome with restriction in the diversity of haplotypes observed (Daly et al., 2001; Rioux et al., 2001; Liu et al., 2004).
That is, single nucleotide polymorphisms found at specific locations within the human genome are inherited in conjunction with nucleotides that can be polymorphic that are physically located near by. In European genomes, allelic association between pairs of markers typically extends over 10-50k, although there is tremendous variability in the magnitude of association observed at any given distance (Clark et al., 1998; Kikuchi et al., 2003; Dunning et al., 2000; Abecasis et al., 2001). Genome-wide data (Gabriel et al., 2002; Reich et al., 2001; Dawson et al., 2002) supports the generality of this description as well as its application across populations. This confirms that measurement of single nucleotide polymorphisms at sites in tight linkage disequilibrium with adjacent genomic regions can provide information about the presence of diversity not just at sites actually measured, but also about large areas of the adjacent genome.

Numerous types of polymorphisms exist and are created when DNA sequences are either inserted or deleted from the genome. Another source of sequence variation results from the presence of repeated sequences in the genome variously termed short tandem repeats (STR), variable number of tandem repeats (VNTR), short sequence repeats (SSR) or microsatellites. These repeats commonly are comprised of 1 to 5 base pairs. Polymorphism occurs due to variation in the number of repeated sequences found at a particular locus.

The most common forrn of genomic variability are single nucleotide polymorphisms or SNPs. SNPs account for as much as 90% of human DNA polymorphism (Collins et al., 1998).
SNPs are single base pair positions in genomic DNA at which different sequence alternatives (genotypes) exist in a population. By common definition, the least frequent allele occurs at least 1%
of the time. These nucleotide substitutions may be a transition, which is the substitution of one purine by another purine or the substitution of one pyrimidine by another, or they may be transversions in which a purine is replaced by a pyrimidine or vice versa.

Typically SNPs are observed in about 1 in 1000 base pairs (Wang et al., 1998;
Taillon-Miller et al., 1999). The frequency of SNPs varies with the type and location of the change.
Specifically, two-thirds of the substitutions involve the C H T (G H A) type, which may occur due to 5-methylcytosine deamination reactions that occur connnonly. SNPs occur at a much higher frequency in non-coding regions than they do in coding regions.

SUMMARY OF THE INVENTION
It has been discovered that polymorphic variations in a number of loci in human genomic DNA are associated with susceptibility to colorectal cancer. This invention thus includes methods for identifying a subject at risk of colorectal and/or determining risk of colorectal cancer in a subject, which comprise detecting the presence or absence of one or more polymorphic variations associated with colorectal cancer in a nucleic acid sample from the subject. In a specific embodiment, this invention relates to identifying an individual who is at altered risk for developing colorectal cancer based on the presence of specific genotypes defined by 25 single nucleotide polymorphism (SNPs), observed alone or in combination.

Through large scale genotyping studies on 2373 blood samples from patients with colon cancer and 2296 control samples from unaffected individuals we have identified 25 polymorphic markers found in 19 genes which are found more frequently in patients with colorectal cancer than in those without this disease. These markers, or those in close linkage disequilibrium, may change the composition, function or abundance of the elements of cellular constituents resulting in a predisposition to colorectal cancer.
Measuring these markers in individuals who do not ostensibly have colon cancer will identify those at heightened risk for the subsequent development of colorectal cancer, providing benefit for, but not limited to, individuals, insurers, care givers and employers. Genes containing colorectal cancer-associated polymorphic markers that we have identified and genes found in linkage disequilibrium with these that we have identified are valuable targets for the development of therapeutics that inhibit or augment the activity of the gene products of these genes for therapeutic use in, but not restricted to, colon cancer. Information obtained from the detection of SNPs associated with colorectal cancer is of great value in the treatment and prevention of this condition.

Accordingly, one aspect of the present invention provides a method for diagnosing a genetic predisposition to colon cancer in a subject, comprising obtaining a sample containing at least one polynucleotide from the subject and analyzing the polynucleotide to detect the genetic polymorphism wherein the presence or absence of the polymorphism is associated with an altered susceptibility to developing colorectal cancer. In one embodiment, one or more of the 25 polymorphisms found distributed among 19 genes that we have identified may be used.

Another aspect of the present invention provides an isolated nucleic acid sequence comprising at least 16 contiguous nucleotides or their complements found in the genomic sequences of the 19 genes adjacent to and including the 25 polymorphic sites the inventors have identified to be associated with colorectal cancer.

Yet another aspect of the invention provides a method for treating colon cancer comprising obtaining a sample of biological material containing at least one polynucleotide from the subject, analyzing the polynucleotides to detect the presence of at least one polymorphism associated with colon cancer and treating the subject in such a way as to counteract the effect of any such polymorphism detected.

Still another aspect of the invention provides a method for the prophylactic treatment of a subject identified with a genetic predisposition to colon cancer identified through the measurement of all or some of the 25 polymorphic SNP markers described in Tables 1 to 25.

Further scope of the applicability of the present invention will become apparent from the detailed description provided below. It should be understood however, that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modification within the spirit and scope of the invention will become apparent to those skilled in the art from the following detailed description.

Tables 1 to 25 report the result of a genotyping analysis of 4669 samples by measuring 99,632 single nucleotide polymorphisms in peripheral blood DNA from 2475 subjects (1234 cases with colorectal cancer and 1241 age matched individuals undiseased at the time of testing), and validating the identified CRC-associated alleles by using peripheral blood DNA from a second, different, group of 2194 subjects (1139 cases with colorectal cancer and 1055 age matched individuals undiseased at the time of testing).

DETAILED DESCRIPTION OF THE INVENTION
It has been discovered that polymorphic variants in a number of sequences, SEQ
ID NOs:1 to 605 are associated with an altered risk of developing colorectal cancer in subjects.
The present invention thus provides SNPs associated with colorectal cancer, nucleic acid molecules containing SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The colorectal cancer-associated SNPs disclosed herein are useful for diagnosing, screening for, and evaluating predisposition to colorectal cancer and related pathologies in humans. Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic agents.

A large number of colorectal cancer-associated SNPs have been identified by genotyping DNA from 4669 individuals, 2373 of these individuals having been previously diagnosed with colorectal cancer and 2296 being "control" or individuals thought to be free of colorectal cancer.

The present invention thus provides individual SNPs associated with colorectal cancer, genomic sequences (SEQ ID NOs: 606 to 624) containing SNPs, and transcript sequences amino acid sequences.
The invention includes methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing colorectal cancer, methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as colorectal cancer, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment strategy, methods of treating a disorder associated with a variant gene/protein (i.e., therapeutic methods), and methods of using the SNPs of the present invention for human identification.
When the presence in the genome of an individual of a particular base, e.g., adenine, at a particular location in the genome correlates with an increased probability of that individual contracting colorectal cancer vis-a-vis a population not having that base at that location in the genome, that individual is said to be at "increased risk" of contracting colorectal cancer, i.e., to have an increased susceptibility. In certain cases, this effect can be a "dominant" effect in which case such increased probability exists when the base is present in one or the other or both alleles of the individual. In certain cases, the effect can be said to be "recessive", in which case such increased probability exists only when the base is present in both alleles of the individual.

When the presence in the genome of an individual of a particular base, e.g., adenine, at a particular location in the genome decreases the probability of that individual contracting colorectal cancer vis-a-vis a population not having that base at that location in the genome, that individual is said to be at "decreased risk" of contracting colorectal cancer, i.e., to have a decreased susceptibility. Such an allele is sometimes referred to in the art as being "protective". As with increased risk, it is also possible for a decreased risk to be characterized as dominant or recessive.

An "altered risk" means either an increased or a decreased risk.

The genetic analysis detailed below linked colorectal cancer with SNPs in the human genome. A SNP is a particular type of polymorphic site, a polymorphic site being a region in a nucleic acid sequence at which two or more alternative nucleotides are observed in a significant number of individuals from a population. A polymorphic site may be a nucleotide sequence of two or more nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite, for example. A polymorphic site that is two or more nucleotides in length may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more, 20 or more, 30 or more, 50 or more, 75 or more, 100 or more, 500 or more, or about 1000 nucleotides in length, where all or some of the nucleotide sequences differ within the region. Each of the specific polymorphic sites found in SEQ ID NOs:606 to 624 is a "single nucleotide polymorphism" or a "SNP."

Where there are two, three, or four alternative nucleotide sequences at a polymorphic site, each nucleotide sequence is referred to as a "polymorphic variant" or "nucleic acid variant." Where two polymorphic variants exist, for example, the polymorphic variant represented in a majority of samples from a population is sometimes referred to as a "prevalent allele" and the polymorphic variant that is less prevalently represented is sometimes referred to as an "uncommon allele."
An individual who possesses two prevalent alleles or two unconunon alleles is "homozygous" with respect to the polymorphism, and an individual who possesses one prevalent allele and one uncommon allele is "heterozygous" with respect to the polymorphism. Individuals who are homozygous with respect to one allele are sometimes predisposed to a different phenotype as compared to individuals who are heterozygous or homozygous with respect to another allele.

A genotype or polymorphic variant may also be expressed in terms of a "haplotype," which refers to the identiy of two or more polymorphic variants occurring within genomic DNA on the same strand of DNA. For example, two SNPs may exist within a gene where each SNP position may include a cytosine variation or an adenine variation. Certain individuals in a population may carry an allele (heterozygous) or two alleles (homozygous) having the gene with a cytosine at each SNP position. As the two cytosines corresponding to each SNP in the gene travel together on one or both alleles in these individuals, the individuals can be characterized as having a cytosine/cytosine haplotype with respect to the two SNPs in the gene.

A "phenotype" is a trait which can be compared between individuals, such as presence or absence of a condition, for example, occurrence of colorectal cancer.

Polymorphic variants are often reported without any determination of whether the variant is represented in a significant fraction of a population. Some reported variants are sequencing errors and/or not biologically relevant. Thus, it is often not known whether a reported polymorphic variant is statistically significant or biologically relevant until the presence of the variant is detected in a population of individuals and the frequency of the variant is determined.

A polymorphic variant may be detected on either or both strands of a double-stranded nucleic acid.
Also, a polymorphic variant may be located within an intron or exon of a gene or within a portion of a regulatory region such as a promoter, a 5' untranslated region (UTR), a 3"
UTR, and in DNA (e.g., genomic DNA (gDNA) and complementary DNA (cDNA)), RNA (e.g., mRNA, tRNA, and rRNA), or a polypeptide. Polymorphic variations may or may not result in detectable differences in gene expression, polypeptide structure, or polypeptide function.

In our genetic analysis associating colorectal cancer with the polymorphic variants set forth in the tables, samples from individuals having been diagnosed with colorectal cancer and individuals not having cancer were allelotyped and genotyped. The allele frequency for each polymorphic variant among cases and controls was determined. These allele frequencies were compared in cases and controls, or combinations. Particular SNPs were thus found to be associated with colorectal cancer when genotype and haplotype frequency differences calculated between case and control pools were established to be statistically significant.

As mentioned above, polymorphic variants can travel together. Such variants are said to be in "linkage disequilibrium" so that heritable elements e.g., alleles that have a tendency to be inherited together instead of being inherited independently by random assortment are in linkage disequilibrium. Alleles are randomly assorted or inherited independently of each other if the frequency of the two alleles together is the product of the frequencies of the two alleles individually.
For example, if two alleles at different polymorphic sites are present in 50% of the chromosomes in a population, then they would be said to assort randomly if the two alleles are present together on 25% of the chromosomes in the population. A higher percentage would mean that the two alleles are linked.
For example, a first polymorphic site PI having two alleles, e.g. A and C--each appearing in 50% of the individuals in a given population, is said to be in linkage disequilibrium with a second polymorphic site P2 having two alleles e.g. G and T--each appearing in 50% of the individuals in a given population, if particular combinations of alleles are observed in individuals at a frequency greater than 25% (if the polymorphic sites are not linked, then one would expect a 50% chance of an individual having A at P 1 and a 50%
chance of having G at P2 thus leading to a 25% chance of having the combination of A at P 1 and G at P2 together). Heritable elements that are in linkage disequilibrium are said to be "linked" or "genetically linked" to each other.

One can see that in the case of a group of SNPs that are in linkage disequilibrium with each other, knowledge of the existence of all such SNPs in a particular individual generally provides redundant information. Thus, when identifying an individual who has an altered risk for developing colorectal cancer according to this invention, it is necessary to detect only one SNP of such a group of SNPs associated with an altered risk of developing colorectal cancer.

It has been shown that each SNP in the genomic sequences identified as SEQ ID
NOs:606 to 624 is associated with the occurrence of colorectal cancer. Thus, featured herein are methods for identifying a risk of colorectal cancer in a subject, which includes detecting the presence or absence of one or more of the SNPs described herein in a human nucleic acid sample.

Three different analyses were performed for each marker and significant results reported below as follows: (a) a test of trend across the 3 genotypes (Sasieni et al. 1997), (b) a dominant model where the homozygous genotype for allele "B" is combined with the prevalent heterozygote genotype; and (c) a recessive model where the homozygous genotype for allele "A" is combined with the heterozygous genotype. An empirical p-value for the largest of these three test statistics was calculated by permutations. In addition, a Mantel-Haenszel odds ratio measuring the change in risk associated with each additional copy of allele B is also calculated and reported.

Pertinent results for each SNP are sununarized in the tables: Chromosomal number and position- using the International Human Genome Sequencing Consortium build 35 (http://www.ncbi.nlm.nih.gov/genome/seq/) as made available by the National Center for Biotechnology Information (NCBI), National Library of Medicine, Building 38A, Bethesda, Maryland 20894 U.S.A., gene marker name-using the nomenclature of the NCBI dbSNP
(http://www.ncbi.nlm.nih.gov/SNP/) and gene name-using the unigene naming convention. Under the "Case Flag" the number 1 designates Cases and the number 0 designates Controls. The identity of the base designated "A" in the analysis is indicated where 1= A (adenine), 2 = C
(cytosine), 3 = G
(guanine) and 4 = T (thymidine). "B" indicates the polymorphic allele. AA, AB, BB are the counts of the number of individuals with the given genotype, by cases/controls. The odds ratio is the Mantel-Haenszel odds ratio across the three genotypes.

It has been discovered that each polymorphic variation in the genomic sequences identified as SEQ ID
NOs:606 to 624 is associated with the occurrence of colorectal cancer. Thus, featured herein are methods for identifying a risk of colorectal cancer in a subject, which comprises detecting the presence or absence of one or more of the polymorphic variations described herein in a human nucleic acid sample. The polymorphic variation, SNP, are detailed in the tables.

Methods for determining whether a subject is susceptible to, i.e., at risk of colorectal cancer are provided herein. These methods include detecting the presence or absence of one or more polymorphic variations, i.e., SNPs, associated with colorectal cancer in a sample from a subject.

SNPs can be associated with a disease state in humans or in animals. The association can be direct, as in conditions where the substitution of a base results in alteration of the protein coding sequence of a gene which contributes directly to the pathophysiology of the condition. Common examples of this include diseases such as sickle cell anemia and cystic fibrosis. The association can be indirect when the SNP
plays no role in the disease, but is located close to the defective gene such that there is a strong association between the presence of the SNP and the disease state. Because of the high frequency of SNPs within the genome, there is a greater probability that a SNP will be linked to a genetic locus of interest than other types of genetic markers.

Disease-associated SNPs can occur in coding and non-coding regions of the genome. When located in the coding region altered function of the ensuing protein sequence may occur.
If it occurs in the regulatory region of a gene it may affect expression of the protein. If the protein is involved in protecting the body against pathological conditions this can result in disease susceptibility.
Numerous methods exist for the measurement of specific SNP genotypes.
Individuals carrying mutations in one or more SNPs of the present invention may be detected at the DNA level by a variety of techniques. Nucleic acids for diagnosis may be obtained from a patient's cells, such as from blood, urine, saliva, tissue biopsy and autopsy material.

The genomic DNA may be used directly for detection or may be amplified enzymatically by using PCR
prior to analysis (Saiki et al., 1986). RNA or cDNA may also be used in the same ways. As an example, PCR primers complementary to the nucleic acid of one or more SNPs of the present invention can be used to identify and analyze the presence or absence of the SNP. For example, deletions and insertions can be detected by a change in size of the amplified product in comparison to the normal genotype.

Point mutations can be identified by hybridizing amplified DNA to radiolabeled SNP RNA of the present invention or alternatively, radiolabeled SNP antisense DNA sequences of the present invention.
Perfectly matched sequences can be distinguished from mismatched duplexes by RNase A digestion or by differences in melting temperatures.

Sequence differences between a reference gene and genes having mutations also may be revealed by direct DNA sequencing. In addition, cloned DNA segrnents may be employed as probes to detect specific DNA segments. The sensitivity of such methods can be greatly enhanced by appropriate use of PCR or another amplification method. For example, a sequencing primer is used with double-stranded PCR product or a single-stranded template molecule generated by a modified PCR. The sequence determination is performed by conventional procedures with radiolabeled nucleotide or by automatic sequencing procedures with fluorescent-tags.

Genetic testing based on DNA sequence differences may be achieved by detection of alteration in electrophoretic mobility of DNA fragments in gels, with or without denaturing agents. Small sequence deletions and insertions can be visualized by high resolution gel electrophoresis. DNA fragments of different sequences may be distinguished on denaturing formamide gradient gels in which the mobilities of different DNA fragments are retarded in the gel at different positions according to their specific melting or partial melting temperatures (Myers et al., 1985).

Sequence changes at specific locations also may be revealed by nuclease protection assays, such as RNase and S 1 protection or the chemical cleavage method (Cotton et al., 1988).

Thus, the detection of a specific DNA sequence may be achieved by methods which include, but are not limited to, hybridization, RNase protection, chemical cleavage, direct DNA
sequencing or the use of restriction enzymes, (e.g., restriction fragment length polymorphisms ("RFLP") and Southern blotting of genomic DNA).

In addition to more conventional gel-electrophoresis and DNA sequencing, mutations also can be detected by in situ analysis.

Genetic mutations can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density arrays containing hundreds or thousands of oligonucleotides probes (Cronin et al., 1996; Kozal et al., 1996). For example, genetic mutations can be identified in two-dimensional arrays containing light-generated DNA probes as described in Cronin et al., supra.
Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.
Specific mutations can also be determined through direct sequencing of one or both strands of DNA
using dideoxy nucleotide chain termination chemistry, electrophoresis through a semi-solid matrix and fluorescent or radioactive chain length detection techniques. Further mutation detection techniques may involve differential susceptibility of the polymorphic double strand to restriction endonuclease digestion, or altered electrophoretic gel mobility of single or double stranded gene fragments containing one polymorphic form. Other techniques to detect specific DNA polymorphisms or mutation may involve evaluation of the structural characteristics at the site of polymorphism using nuclear magnetic resonance or x-ray diffraction techniques.

These genetic tests are useful for prognosing and/or diagnosing colorectal cancer and often are useful for determining whether an individual is at an increased or decreased risk of developing or having colorectal cancer.

Thus, the invention includes a method for identifying a subject at risk of colorectal cancer, which includes detecting in a nucleic acid sample from the subject the presence or absence of a SNP
associated with colorectal cancer at a polymorphic site in a nucleotide sequence identified as SEQ ID
NOs:1 to 624.

Results from prognostic tests may be combined with other test results to diagnose colorectal cancer. For example, prognostic results may be gathered, a patient sample may be ordered based on a determined predisposition to colorectal cancer, the patient sample analyzed, and the results of the analysis may be utilized to diagnose colorectal cancer. Also colorectal cancer diagnostic methods can be developed from studies used to generate prognostic/diagnostic methods in which populations are stratified into subpopulations having different progressions of colorectal cancer. In another embodiment, prognostic results may be gathered; a patient's risk factors for developing colorectal cancer analyzed (e.g., age, family history); and a patient sample may be ordered based on a determined predisposition to colorectal cancer. In an alternative embodiment, the results from predisposition analyses may be combined with other test results indicative of colorectal cancer, which were previously, concurrently, or subsequently gathered with respect to the predisposition testing. In these embodiments, the combination of the prognostic test results with other test results can be probative of colorectal cancer, and the combination can be utilized as a colorectal cancer diagnostic.

Risk of colorectal cancer sometimes is expressed as a probability, such as an odds ratio, percentage, or risk factor. The risk is based upon the presence or absence of one or more of the SNP variants described herein, and also may be based in part upon phenotypic traits of the individual being tested. Methods for calculating risk based upon patient data are well known (Agresti, 2001).
Allelotyping and genotyping analyses may be carried out in populations other than those exemplified herein to enhance the predictive power of the prognostic method. These further analyses are executed in view of the exemplified procedures described herein, and may be based upon the same polymorphic variations or additional polymorphic variations. Risk determinations for colorectal cancer are useful in a variety of applications. In one embodiment, colorectal cancer risk determinations are used by clinicians to direct appropriate detection, preventative and treatment procedures to subjects who most require these. In another embodiment, colorectal cancer risk determinations are used by health insurers for preparing actuarial tables and for calculating insurance premiums.

The nucleic acid sample typically is isolated from a biological sample obtained from a subject. For example, nucleic acid can be isolated from blood, saliva, sputum, urine, cell scrapings, and biopsy tissue. The nucleic acid sample can be isolated from a biological sample using standard techniques. The nucleic acid sample may be isolated from the subject and then directly utilized in a method for determining the presence of a polymorphic variant, or alternatively, the sample may be isolated and then stored (e.g., frozen) for a period of time before being subjected to analysis.

The presence or absence of a polymorphic variant is determined using one or both chromosomal complements represented in the nucleic acid sample. Determining the presence or absence of a polymorphic variant in both chromosomal complements represented in a nucleic acid sample is useful for determining the zygosity of an individual for the polymorphic variant (i.e., whether the individual is homozygous or heterozygous for the polymorphic variant). Any oligonucleotide-based diagnostic may be utilized to determine whether a sample includes the presence or absence of a polymorphic variant in a sample. For example, primer extension methods, ligase sequence determination methods (e.g., U.S.
Pat. Nos. 5,679,524 and 5,952,174, and WO 01/27326), mismatch sequence determination methods (e.g., U.S. Pat. Nos. 5,851,770; 5,958,692; 6,110,684; and 6,183,958), microarray sequence determination methods, restriction fragment length polymorphism (RFLP), single strand conformation polymorphism detection (SSCP) (e.g., U.S. Pat. Nos. 5,891,625 and 6,013,499), PCR-based assays (e.g., TAQMANTM PCR System (Applied Biosystems)), and nucleotide sequencing methods may be used.

Oligonucleotide extension methods typically involve providing a pair of oligonucleotide primers in a polymerase chain reaction (PCR) or in other nucleic acid amplification methods for the purpose of amplifying a region from the nucleic acid sample that comprises the polymorphic variation. One oligonucleotide primer is complementary to a region 3' of the polymorphism and the other is complementary to a region 5' of the polymorphism. A PCR primer pair may be used in methods disclosed in U.S. Pat. Nos. 4,683,195; 4,683,202, 4,965,188; 5,656,493;
5,998,143; 6,140,054; WO
01/27327; and WO 01/27329 for example. PCR primer pairs may also be used in any commercially available machines that perform PCR, such as any of the GENEAMPTM, systems available from Applied Biosystems. Also, those of ordinary skill in the art will be able to design oligonucleotide primers based upon the nucleotide sequences set forth in SEQ ID NOs:1 to 624.

Also provided is an extension oligonucleotide that hybridizes to the amplified fragment adjacent to the polymorphic variation. An adjacent fragmen refers to the 3' end of the extension oligonucleotide being often I nucleotide from the 5' end of the polymorphic site, and sometimes 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the 5' end of the polymorphic site, in the nucleic acid when the extension oligonucleotide is hybridized to the nucleic acid. The extension oligonucleotide then is extended by one or more nucleotides, and the number and/or type of nucleotides that are added to the extension oligonucleotide determine whether the polymorphic variant is present.
Oligonucleotide extension methods are disclosed, for example, in U.S. Pat. Nos. 4,656,127; 4,851,331;
5,679,524; 5,834,189;
5,876,934; 5,908,755; 5,912,118; 5,976,802; 5,981,186; 6,004,744; 6,013,431;
6,017,702; 6,046,005;
6,087,095; 6,210,891; and WO 01/20039. Oligonucleotide extension methods using mass spectrometry are described, for example, in U.S. Pat. Nos. 5,547,835; 5,605,798; 5,691,141;
5,849,542; 5,869,242;
5,928,906; 6,043,031; and 6,194,144. Multiple extension oligonucleotides may be utilized in one reaction, which is referred to as multiplexing.

A microarray can be utilized for determining whether a SNP is present or absent in a nucleic acid sample. A microarray may include any oligonucleotides described herein, and methods for making and using oligonucleotide microarrays suitable for diagnostic use are disclosed in U.S. Pat. Nos. 5,492,806;
5,525,464; 5,589,330; 5,695,940; 5,849,483; 6,018,041; 6,045,996; 6,136,541;
6,142,681; 6,156,501;
6,197,506; 6,223,127; 6,225,625; 6,229,911; 6,239,273; WO 00/52625; WO
01/25485; and WO
01/29259. The microarray typically comprises a solid support and the oligonucleotides may be linked to this solid support by covalent bonds or by non-covalent interactions. The oligonucleotides may also be linked to the solid support directly or by a spacer molecule. A microarray may comprise one or more oligonucleotides complementary to a SNP set forth in the tables.

A kit also may be utilized for determining whether a polymorphic variant is present or absent in a nucleic acid sample. A kit can include one or more pairs of oligonucleotide primers useful for amplifying a fragment of a nucleotide sequence of interest, where the fragment includes a polymorphic site. The kit sometimes comprises a polymerizing agent, for example, a thermostable nucleic acid polymerase such as one disclosed in U.S. Pat. Nos. 4,889,818 or 6,077,664.
Also, the kit often comprises an elongation oligonucleotide that hybridizes to the nucleotide sequence in a nucleic acid sample adjacent to the polymorphic site. Where the kit includes an elongation oligonucleotide, it can also include chain elongating nucleotides, such as dATP, dTTP, dGTP, dCTP, and dITP, including analogs of dATP, dTTP, dGTP, dCTP and dITP, provided that such analogs are substrates for a thermostable nucleic acid polymerase and can be incorporated into a nucleic acid chain elongated from the extension oligonucleotide. Along with chain elongating nucleotides would be one or more chain terminating nucleotides such as ddATP, ddTTP, ddGTP, ddCTP. The kit can include one or more oligonucleotide primer pairs, a polymerizing agent, chain elongating nucleotides, at least one elongation oligonucleotide, and one or more chain terminating nucleotides. Kits optionally include buffers, vials, microtiter plates, and instructions for use.

An individual identified as being susceptible to colorectal cancer may be heterozygous or homozygous with respect to the allele associated with an increased risk of colorectal cancer, as indicated in the tables. A subject homozygous for an allele associated with an increased risk of colorectal cancer is at a comparatively high risk of colorectal cancer as far as that SNP is concerned whether or not the allelic effect has been determined to be dominant or recessive. A subject who is heterozygous for an allele associated with an increased risk of colorectal cancer, in which the allelic effect is recessive would likely be at a comparatively reduced risk of colorectal cancer predicted by that SNP.

Individuals carrying mutations in one or more SNP of the present invention may be detected at the protein level by a variety of techniques. Cells suitable for diagnosis may be obtained from a patient's blood, urine, saliva, tissue biopsy and autopsy material.

Also featured are methods for determining risk of colorectal cancer and/or identifying a subject at risk of colorectal cancer by contacting a polypeptide or protein encoded by a nucleotide sequence from a subject with an antibody that specifically binds to an epitope associated with an altered, usually increased risk of colorectal cancer in the polypeptide.
Isolated Nucleic Acids Oligonucleotides can be linked to a second moiety, which can be another nucleic acid molecule to provide, for example, a tail sequence (e.g., a polyadenosine tail), an adapter sequence (e.g., phage M13 universal tail sequence), etc. Alternatively, the moiety might be one that facilitates linkage to a solid support or a detectable label, e.g., a radioactive label, a fluorescent label, a chemiluminescent label, a paramagnetic label, etc.

Nucleic acid sequences shown in the tables can be used for diagnostic purposes for detection and control of polypeptide expression. Also, oligonucleotide sequences such as antisense RNA, small-interfering RNA (siRNA) and DNA molecules and ribozymes that function to inhibit translation of a polypeptide are part of this invention.

Antisense RNA and DNA molecules, siRNA and ribozymes can be prepared by known methods. These include techniques for chemically synthesizing oligodeoxyribonucleotides such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding the antisense RNA molecule. Such DNA sequences can be incorporated into vectors which incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters, or antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be introduced stably into cell lines.

DNA encoding a polypeptide can also be used in the diagnosis of colorectal cancer, resulting from aberrant expression of a target gene. For example, the nucleic acid sequence can be used in hybridization assays of biopsies or autopsies to diagnose abnormalities of expression or function (e.g., Southern or Northern blot analysis, in situ hybridization assays).

Expression of a polypeptide during embryonic development can also be determined using nucleic acid encoding the polypeptide, particularly production of a functionally impaired polypeptide that is the cause of colorectal cancer. In situ hybridizations using a polypeptide as a probe can be employed to predict problems related to colorectal cancer. Administration of human active polypeptide, recombinantly produced can be used to treat disease states related to functionally impaired polypeptide.
Alternatively, gene therapy approaches may be employed to remedy deficiencies of functional polypeptide or to replace or compete with a dysfunctional polypeptide.

Included as part of this invention are nucleic acid vectors, often expression vectors, which contain a nucleotide sequence set forth in the tables. A vector is a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked and can include a plasmid, cosmid, or viral vector. The vector can be capable of autonomous replication or it can integrate into a host DNA. Viral vectors may include replication defective retroviruses, adenoviruses and adeno-associated viruses for example.

A vector can include a nucleotide sequence from the tables in a form suitable for expression of an encoded protein or nucleic acid in a host cell. The recombinant expression vector generally includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. A
regulatory sequence includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence, as well as tissue-specific regulatory and/or inducible sequences. The design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of polypeptide desired, etc. Expression vectors can be introduced into host cells to produce the desired polypeptides, including fusion polypeptides.

Recombinant expression vectors can be designed for expression of polypeptides in prokaryotic or eukaryotic cells. For example, the polypeptides can be expressed in E. coli, insect cells (e.g., using baculovirus expression vectors), yeast cells, or mammalian cells. Suitable host cells are discussed further by Goeddel (Goeddel, 1990).A recombinant expression vector can also be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

Expression of polypeptides in prokaryotes can be carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion polypeptides.
Fusion vectors add a number of amino acids to a polypeptide. Such fusion vectors typically serve to increase expression of recombinant polypeptide, to increase the solubility of the recombinant polypeptide and/or to aid in the purification of the recombinant polypeptide by acting as a ligand during purification. Often, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant polypeptide to enable separation of the recombinant polypeptide from the fusion moiety after purification of the fusion polypeptide. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX
(Pharmacia Biotech Inc; (Smith & Johnson, 1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding polypeptide, or polypeptide A, respectively, to the target recombinant polypeptide.

Purified fusion polypeptides can be used in screening assays and to generate antibodies specific for polypeptides. In a therapeutic embodiment, fusion polypeptide expressed in a retroviral expression vector can be used to infect bone marrow cells that are subsequently transplanted into irradiated recipients. The pathology of the subject recipient is then examined after sufficient time has passed.
Expressing a polypeptide in host bacteria with an impaired capacity to proteolytically cleave the recombinant polypeptide can be used to maximize recombinant polypeptide expression (Gottesman, 1990). The nucleotide sequence of the nucleic acid to be inserted into an expression vector can be changed so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et al., 1992).

When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. Recombinant mammalian expression vectors can be capable of directing expression of the nucleic acid in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Examples of suitable tissue-specific promoters include an albumin promoter (Pinkert et al., 1987), lymphoid-specific promoters (Calame and Eaton, 1988) (Winoto and Baltimore, 1989), promoters of immunoglobulins (Banerji et al., 1983; Queen and Baltimore, 1983), neuron-specific promoters (Byrne and Ruddle, 1989), pancreas-specific promoters (Edlund et al., 1985), and mammary gland-specific promoters (e.g., milk whey promoter; U.S.
Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are sometimes utilized, for example, the murine hox promoters (Kessel and Gruss, 1990) and the .alpha.-fetopolypeptide promoter (Camper and Tilghman, 1989).

A nucleic acid from one of the tables might be cloned into an expression vector in an antisense orientation. Regulatory sequences (e.g., viral promoters and/or enhancers) operatively linked to a nucleic acid cloned in the antisense orientation can be chosen for directing constitutive, tissue specific or cell type specific expression of antisense RNA in a variety of cell types.
Antisense expression vectors can be in the form of a recombinant plasmid, phagemid or attenuated virus.

The invention includes host cells having a nucleotide sequence from the tables within a recombinant expression vector or a fragment of such a sequence which facilitate homologous recombination into a specific site of the host cell genome. Terms such as host cell and recombinant host cell refer not only to the particular subject cell but also to the progeny of a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell. A host cell can be any prokaryotic or eukaryotic cell. For example, a polypeptide can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells).

Vectors can be introduced into host cells via conventional transformation or transfection techniques.
The terms transformation and transfection refer to a variety of techniques known for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, transduction/infection, DEAE-dextran-mediated transfection, lipofection, or electroporation.

A host cell can be used to produce a polypeptide. Accordingly, methods for producing a polypeptide using the host cells are included as part of this invention. Sucha a method can include culturing host cells into which a recombinant expression vector encoding a polypeptide has been introduced in a suitable medium such that the polypeptide is produced. The method can further include isolating the polypeptide from the medium or the host cell.

The invention also includes cells or purified preparations of cells which include a transgene from the tables, or which otherwise misexpress a polypeptide. Cell preparations can consist of human or non-human cells, e.g., rodent cells, e.g., mouse or rat cells, rabbit cells, or pig cells. The transgene can be misexpressed, e.g., overexpressed or underexpressed. In other embodiments, the cell or cells include a gene which misexpress an endogenous polypeptide (e.g., expression of a gene is disrupted, also known as a knockout). Such cells can serve as a model for studying disorders which are related to mutated or mis-expressed alleles or for use in drug screening. Also provided are human cells (e.g., hematopoietic stem cells) transformed with a nucleic acid from the tables.

The invention includes cells or a purified preparation thereof (e.g., human cells) in which an endogenous nucleic acid from the tables is under the control of a regulatory sequence that does not normally control the expression of the endogenous gene corresponding to the sequence. The expression characteristics of an endogenous gene within a cell (e.g., a cell line or microorganism) can be modified by inserting a heterologous DNA regulatory element into the genome of the cell such that the inserted regulatory element is operably linked to the corresponding endogenous gene.
For example, an endogenous corresponding gene (e.g., a gene which is transcriptionally silent, not normally expressed, or expressed only at very low levels) may be activated by inserting a regulatory element which is capable of promoting the expression of a normally expressed gene product in that cell. Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, U.S. Pat. No. 5,272,071; WO 91/06667, published on May 16, 1991.

Non-human transgenic animals that express a heterologous polypeptide (e.g., expressed from a nucleic acid from the tables) can be generated. Such aninzals are useful for studying the function and/or activity of a polypeptide and for identifying and/or evaluating modulators of the activity of the nucleic acids and encoded polypeptides. A transgenic animal is a non-human animal such as a mammal (e.g., a non-human primate such as chimpanzee, baboon, or macaque; an ungulate such as an equine, bovine, or caprine; or a rodent such as a rat, a mouse, or an Israeli sand rat), a bird (e.g., a chicken or a turkey), an amphibian (e.g., a frog, salamander, or newt), or an insect (e.g., Drosophila melanogaster), in which one or more of the cells of the animal includes a transgene. A transgene is exogenous DNA or a rearrangement (e.g., a deletion of endogenous chromosomal DNA) that is often integrated into or occurs in the genome of cells in a transgenic animal. A transgene can direct expression of an encoded gene product in one or more cell types or tissues of the transgenic animal.
Thus, a transgenic animal can be one in which an endogenous nucleic acid homologous to a nucleic acid from the tables has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal (e.g., an embryonic cell of the animal) prior to development of the animal.

Intronic sequences and polyadenylation signals can also be included in the transgene to increase expression efficiency of the transgene. One or more tissue-specific regulatory sequences can be operably linked to a nucleotide sequence from the tables to direct expression of an encoded polypeptide to particular cells. A transgenic founder animal can be identified based upon the presence of the nucleotide sequence in its genome and/or expression of encoded mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a nucleotide sequence can further be bred to other transgenic animals carrying other transgenes.

Polypeptides can be expressed in transgenic animals or plants by introducing a nucleic acid encoding the polypeptide into the genome of an animal. In certain embodiments the nucleic acid is placed under the control of a tissue specific promoter, e.g., a milk or egg specific promoter, and recovered from the milk or eggs produced by the animal. Also included is a population of cells from a transgenic animal.

Isolated polypeptides encoded by a nucleotide sequence from the tables can be synthesized. Isolated polypeptides include both the full-length polypeptide and the mature polypeptide (i.e., the polypeptide minus the signal sequence or propeptide domain). An isolated, or purified, polypeptide or protein is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or is substantially free from chemical precursors or other chemicals when chemically synthesized. Substantially free means a preparation of a polypeptide having less than about 5% (by dry weight) of contaminating protein, or of chemical precursors or non-target chemicals. When the desired polypeptide is recombinantly produced, it is typically substantially free of culture medium, specifically, where culture medium represents less than about 10% of the polypeptide preparation.
Also, polypeptides may exist as chimeric or fusion polypeptides. As used herein, a"target chimeric polypeptide" or "target fusion polypeptide" includes a target polypeptide linked to a different polypeptide. The target polypeptide in the fusion polypeptide can correspond to an entire or nearly entire polypeptide as it exists in nature or a fragment thereof. The other polypeptide can be fused to the N-terminus or C-terminus of the target polypeptide.

Fusion polypeptides can include a moiety having high affinity for a ligand.
For example, the fusion polypeptide can be a GST-target fusion polypeptide in which the target sequences are fused to the C-terminus of the GST sequences, or a polyhistidine-target fusion polypeptide in which the target polypeptide is fused at the N- or C-terminus to a string of histidine residues. Such fusion polypeptides can facilitate purification of recombinant target polypeptide. Expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide), and a nucleotide sequence from the tables, or a substantially identical nucleotide sequence thereof, can be cloned into an expression vector such that the fusion moiety is linked in-frame to the target polypeptide. Further, the fusion polypeptide can be a target polypeptide containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression, secretion, cellular internalization, and cellular localization of a target polypeptide can be increased through use of a heterologous signal sequence. Fusion polypeptides can also include all or a part of a serum polypeptide (e.g., an IgG
constant region or human serum albumin).

Target polypeptides can be incorporated into pharmaceutical compositions and administered to a subject in vivo. Administration of these polypeptides can be used to affect the bioavailability of a substrate of the polypeptide and may effectively increase polypeptide biological activity in a cell.
Target fusion polypeptides may be useful therapeutically for the treatment of disorders caused by, for example, (i) aberrant modification or mutation of a gene encoding a polypeptide; (ii) mis-regulation of the gene encoding the polypeptide; and (iii) aberrant post-translational modification of a polypeptide.
Also, target polypeptides can be used as immunogens to produce anti-target antibodies in a subject, to purify the polypeptide ligands or binding partners, and in screening assays to identify molecules which inhibit or enhance the interaction of a polypeptide with a substrate.

Polypeptides can be differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any known modification including specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction;
metabolic synthesis in the presence of tunicamycin; etc. may be used. Additional post-translational modifications include, for example, N-linked or 0-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or 0-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of prokaryotic host cell expression. The polypeptide fragments may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the polypeptide.

Chemically modified derivatives of polypeptides that can provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see e.g., U.S. Pat. No. 4,179,337) are also part of this invention. The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.

The polymer may be of any molecular weight, and may be branched or unbranched.
For polyethylene glycol, the molecular weight often is between about 1 kDa and about 100 kDa for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog).

The polymers can be attached to the polypeptide with consideration of effects on functional or antigenic domains of the polypeptide. There are a number of attachment methods available to those skilled in the art (e.g., EP 0 401 384 (coupling PEG to G-CSF) and Malik et al. (Malik et al., 1992) For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The aniino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues, glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. For therapeutic purposes, the attachment sometimes is at an amino group, such as attachment at the N-terminus or lysine group.

Proteins can be chemically modified at the N-terminus. Using polyethylene glycol, for example, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, and the like), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N-terminus may be accomplished by reductive alkylation, which exploits differential reactivity of different type5 of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achievable.

Applications of Prognostic and Diagnostic Results to Pharmacogenomic Methods Pharmacogenomics is a discipline that involves tailoring a treatment for a subject according to the subject's genotype. For example, based upon the outcome of a prognostic test, a clinician or physician may target pertinent information and preventative or therapeutic treatments to a subject who would be benefited by the information or treatment and avoid directing such information and treatments to a subject who would not be benefited (e.g., the treatment has no therapeutic effect and/or the subject experiences adverse side effects). As therapeutic approaches for colorectal cancer continue to evolve and improve, the goal of treatments for colorectal cancer related disorders is to intervene even before clinical signs manifest themselves. Thus, genetic markers associated with susceptibility to colorectal cancer prove useful for early diagnosis, prevention and treatment of colorectal cancer.

The following is an example of a pharmacogenomic embodiment. A particular treatment regimen can exert a differential effect depending upon the subject's genotype. Where a candidate therapeutic exhibits a significant beneficial interaction with a prevalent allele and a comparatively weak interaction with an uncommon allele (e.g., an order of magnitude or greater difference in the interaction), such a therapeutic typically would not be administered to a subject genotyped as being homozygous for the uncommon allele, and sometimes not administered to a subject genotyped as being heterozygous for the uncommon allele. In another example, where a candidate therapeutic is not significantly toxic when administered to subjects who are homozygous for a prevalent allele but is comparatively toxic when administered to subjects heterozygous or homozygous for an uncommon allele, the candidate therapeutic is not typically administered to subjects who are genotyped as being heterozygous or homozygous with respect to the uncommon allele.

Methods of the invention are applicable to pharmacogenomic methods for detecting, preventing, alleviating and/or treating colorectal cancer. For example, a nucleic acid sample from an individual may be subjected to a genetic test. Where one or more SNPs associated with increased risk of colorectal cancer are identified in a subject, information for detecting, preventing or treating colorectal cancer and/or one or more colorectal cancer detection, prevention and/or treatment regimens then may be directed to and/or prescribed to that subject.

In certain embodiments, a detection, preventative and/or treatment regimen is specifically prescribed and/or administered to individuals who will most benefit from it based upon their risk of developing colorectal cancer assessed by the methods described herein. Methods are thus provided for identifying a subject at risk of colorectal cancer and then prescribing a detection, therapeutic or preventative regimen to individuals identified as being at increased risk of colorectal cancer.
Thus, certain embodiments are directed to methods for treating colorectal cancer in a subject, reducing risk of colorectal cancer in a subject, or early detection of colorectal cancer in a subject, which comprise:
detecting the presence or absence of a SNP associated with colorectal cancer in a nucleotide sequence set forth in SEQ ID NOs: 1 to 624, and prescribing or administering a colorectal cancer treatment regimen, preventative regimen and/or detection regimen to a subject from whom the sample originated where the presence of one or more SNPs associated with colorectal cancer are detected in the nucleotide sequence. In these methods, genetic results may be utilized in combination with other test results to diagnose colorectal cancer as described above.

The use of certain colorectal cancer treatments are known in the art, and include surgery, chemotherapy and/or radiation therapy. Any of the treatments may be used in combination to treat or prevent colorectal cancer (e.g., surgery followed by radiation therapy or chemotherapy).

Pharmacogenomics methods also may be used to analyze and predict a response to a colorectal cancer treatment or a drug. For example, if pharmacogenomics analysis indicates a likelihood that an individual will respond positively to a colorectal cancer treatment with a particular drug, the drug may be administered to the individual. Conversely, if the analysis indicates that an individual is likely to respond negatively to treatment with a particular drug, an alternative course of treatment may be prescribed. A negative response may be defined as either the absence of an efficacious response or the presence of toxic side effects. The response to a therapeutic treatment can be predicted in a background study in which subjects in any of the following populations are genotyped: a population that responds favorably to a treatment regimen, a population that does not respond significantly to a treatment regimen, and a population that responds adversely to a treatment regiment (e.g., exhibits one or more side effects). These populations are provided as examples and other populations and subpopulations may be analyzed. Based upon the results of these analyses, a subject is genotyped to predict whether he or she will respond favorably to a treatment regimen, not respond significantly to a treatment regimen, or respond adversely to a treatment regimen.

The methods described herein also are applicable to clinical drug trials. One or more SNPs indicative of response to an agent for treating colorectal cancer or to side effects to an agent for treating colorectal cancer may be identified. Thereafter, potential participants in clinical trials of such an agent may be screened to identify those individuals most likely to respond favorably to the drug and exclude those likely to experience side effects. In that way, the effectiveness of drug treatment may be measured in individuals who respond positively to the drug, without lowering the measurement as a result of the inclusion of individuals who are unlikely to respond positively in the study and without risking undesirable safety problems.

Thus, another embodiment is a method of selecting an individual for inclusion in a clinical trial of a treatment or drug comprising the steps of: (a) obtaining a nucleic acid sample from an individual; (b) determining the identity of a polymorphic variant, e.g., SNP which is associated with a positive response to the treatment or the drug, or at least one SNP which is associated with a negative response to the treatment or the drug in the nucleic acid sample, and (c) including the individual in the clinical trial if the nucleic acid sample contains the SNP associated with a positive response to the treatment or the drug or if the nucleic acid sample lacks said SNP associated with a negative response to the treatment or the drug. The SNP may be in a sequence selected individually or in any combination from those disclosed in the tables. Step (c) can also include administering the drug or the treatment to the individual if the nucleic acid sample contains the SNP associated with a positive response to the treatment or the drug and the nucleic acid sample lacks the SNP associated with a negative response to the treatment or the drug.

Compositions Comprising Colorectal Cancer-Directed Molecules The invention includes a composition made up of a colorectal cancer cell and one or more molecules specifically directed and targeted to a nucleic acid comprising a nucleotide sequence shown in the tables, or a polypeptide encoded thereby. Such directed molecules include, but are not limited to, a compound that binds to a nucleic acid or a polypeptide; a RNAi or siRNA
molecule having a strand complementary to a nucleotide sequence; an antisense nucleic acid complementary to an RNA encoded by a DNA sequence; a ribozyme that hybridizes to a nucleotide sequence; a nucleic acid aptamer that specifically binds a polypeptide; and an antibody that specifically binds to a polypeptide or binds to a nucleic acid. In specific embodiments, the colorectal cancer directed molecule interacts with a nucleic acid or polypeptide variant associated with colorectal cancer.

Compounds Compounds can be obtained using any of numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive (Zuckermann et al., 1994).
Biological library and peptoid library approaches are typically limited to peptide libraries, while the other approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, 1997).
Examples of methods for synthesizing molecular libraries are described, for example, in DeWitt et al.

(DeWitt et al., 1993), Erb et al. (Erb et al., 1994), Zuckermann et al.
(Zuckermann et al., 1994), Cho et al. (Cho et al., 1993) and Gallop et al. (Gallop et al., 1994).

Libraries of compounds may be presented in solution (Houghten et al., 1992), or on beads (Lam et al., 1991), chips (Fodor et al., 1993), bacteria or spores (Ladner, U.S. Pat. No.
5,223,409), plasmids (Cull et al., 1992) or on phage (Scott and Smith, 1990; Devlin et al., 1990; Cwirla et al., 1990; Felici et al., 1991).

A compound sometimes alters expression and sometimes alters activity of a target polypeptide and may be a small molecule. Small molecules include peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e., including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

An antisense nucleic acid refers to a nucleotide sequence complementary to a sense nucleic acid encoding a polypeptide, e.g., complementary to the, coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. The antisense nucleic acid can be complementary to an entire coding strand in a nucleic acid molecule having a sequence of one of SEQ ID
NOs:606 to 624, or to a portion thereof. In another embodiment, the antisense nucleic acid molecule is antisense to a noncoding region of the coding strand of a nucleotide sequence, e.g., 5' and 3' untranslated regions.

An antisense nucleic acid can be designed such that it is complementary to the entire coding region of an mRNA encoded by a nucleotide sequence of interest, and often the antisense nucleic acid is an oligonucleotide antisense to only a portion of a coding or noncoding region of the mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of the mRNA, e.g., between the -10 and +10 regions of the target gene nucleotide (SNP) sequence of interest. An antisense oligonucleotide can be, for example, about 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or more nucleotides in length. The antisense nucleic acids, which include the ribozymes described below, can be designed to target a nucleotide sequence in any of SEQ ID NOs:606 to 624. Uncommon alleles and prevalent alleles can be targeted, and those associated with an increased risk of colon cancer are often designed, tested, and administered to subjects.

An antisense nucleic acid can be constructed using chemical synthesis and enzymatic ligation reactions using standard procedures. For example, an antisense nucleic acid molecule can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Antisense nucleic acid also can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA
transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest.

When utilized as therapeutics, antisense nucleic acids typically are administered to a subject (e.g., by direct injection at a tissue site) or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a polypeptide and thereby inhibit expression of the polypeptide, for example, by inhibiting transcription and/or translation. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then are administered systemically. For systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, for example, by linking antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens.
Antisense nucleic acid molecules can also be delivered to cells using vectors. Sufficient intracellular concentrations of antisense molecules are achieved by incorporating a strong promoter, such as a pol II or pol III
promoter, in the vector construct.

Antisense nucleic acid molecules sometimes are anomeric nucleic acid molecules (Gautier et al., 1987).
Antisense nucleic acid molecules can also comprise a 2'-o-methylribonucleotide (Inoue et al., 1987a) or a chimeric RNA-DNA analogue (Inoue et al., 1987b). Antisense nucleic acids sometimes are composed of DNA or peptide nucleic acid (PNA).

In another embodiment, an antisense nucleic acid is a ribozyme. A ribozyme having specificity for a target nucleotide sequence can include one or more sequences complementary to such a nucleotide sequence, and a sequence having a known catalytic region responsible for mRNA
cleavage (see e.g., U.S. Pat. No. 5,093,246 or Haselhoff and Gerlach (Haseloff and Gerlach, 1988).
For example, a derivative of a Tetrahymena L- 19 IVS RNA is sometimes utilized in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a mRNA (see e.g., Cech et al., U.S. Pat. No. 4,987,071; and Cech et al., U.S. Pat. No. 5,116,742). Also, target mRNA sequences can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA
molecules (Bartel and Szostak, 1993).

Colorectal cancer directed molecules include in certain embodiments nucleic acids that can form triple helix structures with a target nucleotide sequence, especially one that includes a regulatory region that controls expression of a polypeptide. Gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of a target nucleotide sequence (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of a gene in target cells (Helene, 1991; Helene et al., 1992; Maher, III, 1992). Potential sequences that can be targeted for triple helix formation can be increased by creating a switchback nucleic acid molecule. Switchback molecules are synthesized in an alternating 5'-3',3'-5' manner, such that they base pair with first one strand of a duplex and then the other, eliminating the necessity for a sizeable stretch of either purines or pyrimidines to be present on one strand of a duplex.

Colorectal cancer directed molecules include RNAi and siRNA nucleic acids.
Gene expression may be inhibited by the introduction of double-stranded RNA (dsRNA), which induces potent and specific gene silencing, a phenomenon called RNA interference or RNAi. See, e.g., Fire et al., U.S. Pat. No.
6,506,559; Tuschl et al., PCT International Publication No. WO 01/75164; Kay et al., PCT
International Publication No. WO 03/010180A1; or Bosher J M, Labouesse (Bosher and Labouesse, 2000). This process has been improved by decreasing the size of the double-stranded RNA to 20-24 base pairs (to create small-interfering RNAs or siRNAs) that switched off genes in mammalian cells without initiating an acute phase response, i.e., a host defense mechanism that often results in cell death (Caplen et al., 2001 a) (Elbashir et al., 2002). There is increasing evidence of post-transcriptional gene silencing by RNA interference (RNAi) for inhibiting targeted expression in mammalian cells at the mRNA level, in human cells. There is additional evidence of effective methods for inhibiting the proliferation and migration of tumor cells in human patients, and for inhibiting metastatic cancer development (see, e.g., U.S. patent application No. US2001000993183; Caplen et al. (Caplen et al., 2001b), Abderrahman et al. (Abderrahmani et al., 2001).

An siRNA or RNAi is a nucleic acid that forms a double stranded RNA and has the ability to reduce or inhibit expression of a gene or target gene when the siRNA is delivered to or expressed in the same cell as the gene or target gene. siRNA is short double-stranded RNA formed by the complementary strands.
Complementary portions of the siRNA that hybridize to form the double stranded molecule often have substantial or complete identity to the target molecule sequence. In one embodiment, an siRNA is a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA.

When designing the siRNA molecules, the targeted region often is selected from a given DNA
sequence beginning 50 to 100 nucleotides downstream of the start codon. See, e.g., Elbashir et al.
(Elbashir et al., 2002). Initially, 5' or 3' UTRs and regions nearby the start codon were avoided assuming that UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. Sometimes regions of the target 23 nucleotides in length conforming to the sequence motif AA (N19)TT (N, an nucleotide), and regions with approximately 30% to 70% G/C-content (often about 50% G/C-content) often are selected. If no suitable sequences are found, the search often is extended using the motif NA (N2 1). The sequence of the sense siRNA
sometimes corresponds to (N19) TT or N21 (position 3 to 23 of the 23-nt motif), respectively. In the latter case, the 3' end of the sense siRNA often is converted to TT. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3' overhangs. The antisense siRNA is synthesized as the complement to position 1 to 21 of the 23-nt motif. Because position 1 of the 23-nt motif is not recognized sequence-specifically by the antisense siRNA, the 3'-most nucleotide residue of the antisense siRNA can be chosen deliberately.
However, the penultimate nucleotide of the antisense siRNA (complementary to position 2 of the 23-nt motif) often is complementary to the targeted sequence. For simplifying chemical synthesis, TT often is utilized. siRNAs corresponding to the target motif NAR (N17)YNN, where R is purine (A,G) and Y is pyrimidine (C,U), often are selected. Respective 21 nucleotide sense and antisense siRNAs often begin with a purine nucleotide and can also be expressed from pol III expression vectors without a change in targeting site. Expression of RNAs from pol III promoters can be more efficient when the first transcribed nucleotide is a purine.

The sequence of the siRNA can correspond to the full length target gene, or a subsequence thereof.
Often, the siRNA is about 15 to about 50 nucleotides in length (e.g., each complementary sequence of the double stranded siRNA is 15 to 50 nucleotides in length, and the double stranded siRNA is about 15 to 50 base pairs in length, sometimes about 20 to 30 nucleotides in length or about 20 to 25 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. The siRNA sometimes is about 21 nucleotides in length. Methods of using siRNA are known in the art, and specific siRNA
molecules may be purchased from a number of companies including Dharmacon Research, Inc.

Antisense, ribozyme, RNAi and siRNA nucleic acids can be altered to form modified nucleic acid molecules. The nucleic acids can be altered at base moieties, sugar moieties or phosphate backbone moieties to improve stability, hybridization, or solubility of the molecule.
For example, the deoxyribose phosphate backbone of nucleic acid molecules can be modified to generate peptide nucleic acids (see Hyrup et al., Bioorganic & Medicinal Chemistry 4 (1): 5-23 (1996)). A peptide nucleic acid, or PNA, refers to a nucleic acid mimic such as a DNA mimic, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of a PNA can allow for specific hybridization to DNA and RNA under conditions of low ionic strength. Synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described, for example, in Hyrup et al. (Hyrup and Nielsen, 1996), and Perry-O'Keefe et al. (Abderrahmani et al., 2001).

PNA nucleic acids can be used in prognostic, diagnostic, and therapeutic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, for example, inducing transcription or translation arrest or inhibiting replication. PNA nucleic acid molecules can also be used in the analysis of SNPs in a gene, (e.g., by PNA-directed PCR clamping); as artificial restriction enzymes when used in combination with other enzymes, (e.g., Sl nucleases (Hyrup and Nielsen, 1996) or as probes or primers for DNA sequencing or hybridization (Hyrup and Nielsen, 1996; Perry-O'Keefe et al., 1996).

In other embodiments, oligonucleotides may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across cell membranes (see e.g., Letsinger et al. (Letsinger et al., 1989); Lemaitre et al. (Lemaitre et al., 1987) and PCT Publication No.
W088/09810) or the blood-brain barrier (see, e.g., PCT Publication No.
W089/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents (van der Krol et al., 1988) or intercalating agents (Zon, 1988). To this end, the oligonucleotide may be conjugated to another molecule, (e.g., a peptide, hybridization triggered cross-linking agent, transport agent, or hybridization-triggered cleavage agent).

Also included as part of this invention are molecular beacon oligonucleotide primer and probe molecules having one or more regions complementary to a target nucleotide sequence, two complementary regions one having a fluorophore and one a quencher such that the molecular beacon is useful for quantifying the presence of the nucleic acid in a sample. Molecular beacon nucleic acids are described, for example, in Lizardi et al., U.S. Pat. No. 5,854,033; Nazarenko et al., U.S. Pat. No.
5,866,336, and Livak et al., U.S. Pat. No. 5,876,930.

Antibodies An immunogen typically is used to prepare antibodies by immunizing a suitable subject, (e.g., rabbit, goat, mouse or other mammal). An appropriate inununogenic preparation can contain, for example, recombinantly expressed chemically synthesized polypeptide. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulatory agent.
Amino acid polymorphisms can be detected using antibodies specific for the altered epitope by western analysis after the electrophoresis of denatured proteins. Protein polymorphism can also be detected using fluorescently identified antibodies which bind to specific polymorphic epitopes and detected in whole cells using fluorescence activated cell sorting techniques (FACS).
Polymorphic protein sequence may also be determined by NMR spectroscopy or by x-ray diffraction studies.
Further, determination of polymorphic sites in proteins may be accomplished by observing differential cleavage by specific or non specific proteases.

An antibody is an immunoglobulin molecule or immunologically active portion thereof, i.e., an antigen-binding portion. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab')2 fragments which can be generated by treating the antibody with an enzyme such as pepsin. An antibody can be polyclonal, monoclonal, or recombinant (e.g., a chimeric or humanized), fully human, non-human (e.g., murine), or a single chain antibody. An antibody may have effector function and can fix complement, and is sometimes coupled to a toxin or imaging agent.

A full-length polypeptide or antigenic peptide fragment encoded by a target nucleotide sequence can be used as an immunogen or can be used to identify antibodies made with other immunogens, e.g., cells, membrane preparations, and the like. An antigenic peptide often includes at least 8 amino acid residues of the amino acid sequences encoded by a nucleotide sequence of one of SEQ ID
NOs:606 to 624, and encompasses an epitope. Antigenic peptides sometimes include 10 or more amino acids, 15 or more amino acids, 20 or more amino acids, or 30 or more amino acids. Hydrophilic and hydrophobic fragments of polypeptides sometimes are used as immunogens.

Epitopes encompassed by the antigenic peptide are regions located on the surface of the polypeptide (e.g., hydrophilic regions) as well as regions with high antigenicity. For example, an Emini surface probability analysis of the human polypeptide sequence can be used to indicate the regions that have a particularly high probability of being localized to the surface of the polypeptide and are thus likely to constitute surface residues useful for targeting antibody production. The antibody may bind an epitope on any domain or region on polypeptides for use in the invention.

Also, chimeric, humanized, and completely human antibodies are useful for applications which include repeated administration to subjects. Chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, can be made using standard recombinant DNA
techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques, for example using methods described in Robinson et al., International Application No. PCT/US86/02269;
Akira, et al., European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al., European Patent Application 173,494; Neuberger et al., PCT International Publication No. WO 86/01533; Cabilly et al., U.S. Pat. No. 4,816,567; Cabilly et al., European Patent Application 125,023; (Better et al., 1988; Liu et al., 1987a; Liu et al., 1987b; Sun et al., 1987;
Nishimura et al., 1987) (Wood et al., 1985; Shaw et al., 1988; Morrison, 1985) and Winter U.S. Pat.
No. 5,225,539, (Verhoeyen et al., 1988; Beidler et al., 1988).

Completely human antibodies can be particularly desirable for therapeutic treatment of human patients.
Such antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. See, for example, Lonberg and Huszar (Lonberg and Huszar, 1995) and U.S. Pat. Nos.
5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806. In addition, companies such as Abgenix, Inc. (Fremont, Calif.) and Medarex, Inc. (Princeton, N.J.), can be engaged to provide human antibodies directed against a selected antigen. Completely human antibodies that recognize a selected epitope also can be generated using guided selection. In this approach a selected non-human monoclonal antibody (e.g., a murine antibody) is used to guide the selection of a completely human antibody recognizing the same epitope. This technology is described for example by Jespers et al.
(Jespers et al., 1994).

An antibody can be a single chain antibody. A single chain antibody (scFV) can be engineered (see, e.g., Colcher et al. (Colcher et al., 1999) and Reiter (Reiter and Pastan, 1996). Single chain antibodies can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target polypeptide.

Antibodies also may be selected or modified so that they exhibit reduced or no ability to bind an Fc receptor. For example, an antibody may be an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor (e.g., it has a mutagenized or deleted Fc receptor binding region).
Also, an antibody (or fragment thereof) may be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent or a radioactive metal ion. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1 dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thiotepa chlorambucil, melphalan, carmustine (BCNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).

Antibody conjugates can be used for modifying a given biological response. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, ~-interferon, cx interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors. Also, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980, for example.

An antibody (e.g., monoclonal antibody) can be used to isolate target polypeptides by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, an antibody can be used to detect a target polypeptide (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the polypeptide. Antibodies can be used diagnostically to monitor polypeptide levels in tissue as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, B-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include'zsh 1311, 31S or 3H. Also, an antibody can be utilized as a test molecule for determining whether it can treat colorectal cancer, and as a therapeutic for administration to a subject for treating colorectal cancer.

An antibody can be made by immunizing with a purified antigen, or a fragment thereof, a membrane associated antigen, tissues, e.g., crude tissue preparations, whole cells, preferably living cells, lysed cells, or cell fractions.

Included as part of this invention are antibodies which bind only a native polypeptide, only denatured or otherwise non-native polypeptide, or which bind both, as well as those having linear or conformational epitopes. Conformational epitopes sometimes can be identified by selecting antibodies that bind to native but not denatured polypeptide. Also featured are antibodies that specifically bind to a polypeptide variant associated with colorectal cancer.

Screening Assays The invention includes methods for identifying a candidate therapeutic for treating colorectal cancer.
The methods include contacting a test molecule with a target molecule in a system. A target molecule is a nucleic acid molecule having a sequence of any of SEQ ID NOs: 1 to 624, or a fragment thereof, or an encoded polypeptide of SEQ ID NOs:606 to 624. The method also includes determining the presence or absence of an interaction between the test molecule and the target molecule, where the presence of an interaction between the test molecule and the nucleic acid or polypeptide identifies the test molecule as a candidate colorectal cancer therapeutic. The interaction between the test molecule and the target molecule may be quantified.

Test molecules and candidate therapeutics include compounds, antisense nucleic acids, siRNA
molecules, ribozymes, polypeptides or proteins encoded by target nucleic acids, and immunotherapeutics (e.g., antibodies and HLA-presented polypeptide fragments).
A test molecule or candidate therapeutic may act as a modulator of target molecule concentration or target molecule function in a system. A modulator may agonize (i.e., up-regulates) or antagonize (i.e., down-regulates) a target molecule concentration partially or completely in a system by affecting such cellular functions as DNA replication and/or DNA processing (e.g., DNA methylation or DNA
repair), RNA transcription and/or RNA processing (e.g., removal of intronic sequences and/or translocation of spliced mRNA
from the nucleus), polypeptide production (e.g., translation of the polypeptide from mRNA), and/or polypeptide post-translational modification (e.g., glycosylation, phosphorylation, and proteolysis of pro-polypeptides). A modulator may also agonize or antagonize a biological function of a target molecule partially or completely, where the function may include adopting a certain structural conformation, interacting with one or more binding partners, ligand binding, catalysis (e.g., phosphorylation, dephosphorylation, hydrolysis, methylation, and isomerization), and an effect upon a cellular event (e.g., effecting progression of colorectal cancer).

According to an aspect of this invention a system, i.e., a cell free in vitro environment and a cell-based environment such as a collection of cells, a tissue, an organ, or an organism, is contacted with a test molecule in a variety of manners, including adding molecules in solution and allowing them to interact with one another by diffusion, cell injection, and any administration routes in an animal. An interaction refers to an effect of a test molecule on test molecule, where the effect sometimes is binding between the test molecule and the target molecule, and sometimes is an observable change in cells, tissue, or organism.

There are known methods for detecting the presence or absence of interaction between a test molecule and a target molecule. For example, titrametric, acidimetric, radiometric, NMR, monolayer, polarographic, spectrophotometric, fluorescent, and ESR assays probative of a target molecule interaction may be utilized.

Test molecule/target molecule interactions can be detected and/or quantified using known assays. For example, an interaction can be determined by labeling the test molecule and/or the target molecule, where the label is covalently or non-covalently attached to the test molecule or target molecule. The label is sometimes a radioactive molecule such as125I,13'I, 35S or 3H, which can be detected by direct counting of radioemission or by scintillation counting. Also, enzymatic labels such as horseradish peroxidase, alkaline phosphatase, or luciferase may be utilized where the enzymatic label can be detected by determining conversion of an appropriate substrate to product. In addition, presence or absence of an interaction can be determined without labeling. For example, a microphysiometer (e.g., Cytosensor) is an analytical instrument that measures the rate at which a cell acidifies its environment using a light-addressable potentiometric sensor (LAPS). Changes in this acidification rate can be used as an indication of an interaction between a test molecule and target molecule (McConnell et al., 1992).
In cell-based systems, cells typically include a nucleic acid from SEQ ID NOs:
I to 624 or an encoded polypeptide from SEQ ID NOs:606 to 624, and are often of mammalian origin, although the cell can be of any origin. Whole cells, cell homogenates, and cell fractions (e.g., cell membrane fractions) can be subjected to analysis. Where interactions between a test molecule with a target polypeptide are monitored, soluble and/or membrane bound forms of the polypeptide may be utilized. Where membrane-bound forms of the polypeptide are used, it may be desirable to utilize a solubilizing agent.
Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, TritonTMX-100, TritonTM X-1 14, etc.

An interaction between a test molecule and target molecule also can be detected by monitoring fluorescence energy transfer (FET) (see, e.g., Lakowicz et al., U.S. Pat. No.
5,631,169; Stavrianopoulos et al., U.S. Pat. No. 4,868,103). A fluorophore label on a first, donor molecule is selected such that its emitted fluorescent energy will be absorbed by a fluorescent label on a second, acceptor molecule, which in turn is able to fluoresce due to the absorbed energy. Alternately, the donor polypeptide molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the acceptor molecule label may be differentiated from that of the donor. Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, the spatial relationship between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the acceptor molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter).

In another embodiment, determining the presence or absence of an interaction between a test molecule and a target molecule can be effected by monitoring surface plasmon resonance (Sjolander and Urbaniczky, 1991; Szabo et al., 1995). Surface plasmon resonance (SPR) or biomolecular interaction analysis (BIA) can be utilized to detect biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore). Changes in the mass at the binding surface (indicative of a binding event) result in alterations of the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance, resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules.

In another embodiment, the target molecule or test molecules are anchored to a solid phase, facilitating the detection of target molecule/test molecule complexes and separation of the complexes from free, uncomplexed molecules. The target molecule or test molecule is immobilized to the solid support. In one embodiment, the target molecule is anchored to a solid surface, and the test molecule, which is not anchored, can be labeled, either directly or indirectly, with detectable labels.

It may be desirable to immobilize a target molecule, an anti-target molecule antibody, and/or test molecules to facilitate separation of target molecule/test molecule complexes from uncomplexed forms, as well as to accommodate automation of the assay. The attachment between a test molecule and/or target molecule and the solid support may be covalent or non-covalent (see, e.g., U.S. Pat. No.
6,022,688 for non-covalent attachments). The solid support may be one or more surfaces of the system, such as one or more surfaces in each well of a microtiter plate, a surface of a silicon wafer, a surface of a bead (Lam et al., 1991) that is optionally linked to another solid support, or a channel in a microfluidic device, for example. Types of solid supports, linker molecules for covalent and non-covalent attachments to solid supports, and methods for immobilizing nucleic acids and other molecules to solid supports are known (see, e.g., U.S. Pat. Nos. 6,261,776; 5,900,481;
6,133,436; and 6,022,688;
and WIPO publication WO 01/18234).

In one embodiment, a target molecule may be immobilized to surfaces via biotin and streptavidin. For example, a biotinylated polypeptide can be prepared from biotin-NHS (N-hydroxysuccinimide, e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In another embodiment, a target polypeptide can be prepared as a fusion polypeptide. For example, glutathione-S-transferase/-polypeptide fusion can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtiter plates, which are then combined with a test molecule under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, or the matrix is immobilized in the case of beads, and complex formation is determined directly or indirectly as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of target molecule binding or activity is determined using standard techniques.

In one embodiment, the non-immobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed (e.g., by washing) under conditions such that a significant percentage of complexes formed will remain immobilized to the solid surface. The detection of complexes anchored on the solid surface can be accomplished in a number of manners. Where the previously non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the previously non-immobilized component is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface, e.g., by adding a labeled antibody specific for the inunobilized component, where the antibody, in turn, can be directly labeled or indirectly labeled with, e.g., a labeled anti-Ig antibody.

In another embodiment, an assay is performed utilizing antibodies that specifically bind a target molecule or test molecule but do not interfere with binding of the target molecule to the test molecule.
Such antibodies can be linked to a solid support, and unbound target molecule may be immobilized by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the target molecule, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule.

Cell free assays also can be conducted in a liquid phase. In such an assay, reaction products are separated from unreacted components, by known techniques, including:
differential centrifugation (Rivas and Minton, 1993); electrophoresis (1999) and immunoprecipitation (1999). Media and chromatographic techniques are known (Heegaard, 1998; Hage and Tweed, 1997).
Further, fluorescence energy transfer may also be conveniently utilized to detect binding without further purification of the complex from solution.

In another embodiment, modulators of target molecule expression are identified. For example, a cell or cell free mixture is contacted with a candidate compound and the expression of target mRNA or polypeptide is evaluated relative to the level of expression of target mRNA or polypeptide in the absence of the candidate compound. When expression of target mRNA or polypeptide is greater in the presence of the candidate compound than in its absence, the candidate compound is identified as an agonist of target mRNA or polypeptide expression. Alternatively, when expression of target mRNA or polypeptide is less (e.g., less with statistical significance) in the presence of the candidate compound than in its absence, the candidate compound is identified as an antagonist or inhibitor of target mRNA
or polypeptide expression. The level of target mRNA or polypeptide expression can be determined by methods described herein.

In another embodiment, binding partners that interact with a target molecule are detected. The target molecules can interact with one or more cellular or extracellular macromolecules, such as polypeptides in vivo, and these interacting molecules or binding partners. Binding partners can agonize or antagonize target molecule biological activity. Also, test molecules that agonize or antagonize interactions between target molecules and binding partners can be useful as therapeutic molecules as they can up-regulate or down-regulated target molecule activity in vivo and thereby treat colorectal cancer.

Binding partners of target molecules can be identified by known methods. For example, binding partners may be identified by lysing cells and analyzing cell lysates by electrophoretic techniques.
Alternatively, a two-hybrid assay or three-hybrid assay can be utilized (Zervos et al., 1993; Madura et al., 1993; Bartel et al., 1993; Iwabuchi et al., 1993): see also, e.g., U.S.
Pat. No. 5,283,317 and Brent W094/10300. A two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. The assay often utilizes two different DNA
constructs. In one construct, a nucleic acid from one of SEQ ID NOs:606 to 624, sometimes referred to as the bait, is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In another construct, a DNA sequence from a library of DNA sequences that encodes a potential binding partner, sometimes referred to as the prey, is fused to a gene that encodes an activation domain of the known transcription factor. Sometimes, a target nucleic acid can be fused to the activation domain. If the bait and the prey molecules interact in vivo, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., lacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to identify the potential binding partner.

In an embodiment for identifying test molecules that antagonize or agonize complex formation between target molecules and binding partners, a reaction mixture containing the target molecule and the binding partner is prepared, under conditions and for a time sufficient to allow complex formation. The reaction mixture often is provided in the presence or absence of the test molecule. The test molecule can be included initially in the reaction mixture, or can be added at a time subsequent to the addition of the target molecule and its binding partner. Control reaction mixtures are incubated without the test molecule or with a placebo. Formation of any complexes between the target molecule and the binding partner then is detected. Decreased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture indicates that the molecule antagonizes target molecule/binding partner complex formation. Alternatively, increased formation of a complex in the reaction mixture containing test molecule as compared to in a control reaction mixture, indicates that the molecule agonizes target molecule/binding partner complex formation. In another embodiment, complex formation of target molecule/binding partner can be compared to complex formation of mutant target molecule/binding partner (e.g., amino acid modifications in a target polypeptide). Such a comparison can be important in those cases where it is desirable to identify test molecules that-modulate interactions of mutant but not non-mutated target gene products.

The assays can be conducted in a heterogeneous or homogeneous format. In heterogeneous assays, a target molecule and/or the binding partner are immobilized to a solid phase, and complexes are detected on the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the molecules being tested. For example, test compounds that agonize target molecule/binding partner interactions can be identified by conducting the reaction in the presence of the test molecule in a competition format. Alternatively, test molecules that agonize preformed complexes, e.g., molecules with higher binding constants that displace one of the components from the complex, can be tested by adding the test compound to the reaction mixture after complexes have been formed.

In a heterogeneous assay, the target molecule or the binding partner is anchored onto a solid surface (e.g., a microtiter plate), while the non-anchored species is labeled, either directly or indirectly. The anchored molecule can be immobilized by non-covalent or covalent attachments.
Alternatively, an immobilized antibody specific for the molecule to be anchored can be used to anchor the molecule to the solid surface. The partner of the immobilized species is exposed to the coated surface with or without the test molecule. After the reaction is complete, unreacted components are removed (e.g., by washing) such that a significant portion of any complexes formed will remain immobilized on the solid surface. Where the non-immobilized species is pre-labeled, the detection of label immobilized on the surface is indicative of complex. Where the non-immobilized species is not pre-labeled, an indirect label can be used to detect complexes anchored to the surface; e.g., by using a labeled antibody specific for the initially non-immobilized species. Depending upon the order of addition of reaction components, test compounds that inhibit complex formation or that disrupt preformed complexes can be detected.

The reaction can be conducted in a liquid phase in the presence or absence of test molecule, where the reaction products are separated from unreacted components, and the complexes are detected (e.g., using an immobilized antibody specific for one of the binding components to anchor any complexes formed in solution, and a labeled antibody specific for the other partner to detect anchored complexes). Again, depending upon the order of addition of reactants to the liquid phase, test compounds that inhibit complex or that disrupt preformed complexes can be identified.

In an alternate embodiment, a homogeneous assay can be utilized. For example, a preformed complex of the target gene product and the interactive cellular or extracellular binding partner-product is prepared. One or both of the target molecule or binding partner is labeled, and the signal generated by the label(s) is quenched upon complex formation (e.g., U.S. Pat. No. 4,109,496 that-utilizes this approach for immunoassays). Addition of a test molecule that competes with and displaces one of the species from the preformed complex will result in the generation of a signal above background. In this way, test substances that disrupt target molecule/binding partner complexes can be identified.
Identification of Candidate Therapeutics Candidate therapeutics for treating colorectal cancer are identified from a group of test molecules that interact with a target molecule. Test molecules are normally ranked according to the degree with which they modulate (e.g., agonize or antagonize) a function associated with the target molecule (e.g., DNA
replication and/or processing, RNA transcription and/or processing, polypeptide production and/or processing, and/or biological function/activity), and then top ranking modulators are selected. Also, pharmacogenomic information can determine the rank of a modulator. The top 10%
of ranked test molecules often are selected for further testing as candidate therapeutics, and sometimes the top 15%, 20%, or 25% of ranked test molecules are selected for further testing as candidate therapeutics.
Candidate therapeutics typically are formulated for administration to a subject.
Therapeutic Formulations Formulations and pharmaceutical compositions typically include in combination with a pharmaceutically acceptable carrier one or more target molecule modulators.
The modulator often is a test molecule identified as having an interaction with a target molecule by a screening method. The modulator may be a compound, an antisense nucleic acid, a ribozyme, an antibody, or a binding partner.
Also, formulations may include a polypeptide combination with a pharmaceutically acceptable carrier.
A pharmaceutically acceptable carrier includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. See for example, Remington's Pharmaceutical Sciences (2005).
Supplementary active compounds can also be incorporated into the compositions. Pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

A pharmaceutical composition typically is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administrations Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH
can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
The composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation often utilized are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Systemic administration might be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
Molecules can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, active molecules are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
Methods for preparation of such formulations will be apparent to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, lnc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S.
Pat. No. 4,522,811.

It is advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Each unit containing a predetermined quantity of active compound is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population).
The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD5(,/ED50. Molecules which exhibit high therapeutic indices often are utilized. While molecules that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such molecules typically lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any molecules used in methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC₅₀ (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

As defined herein, a therapeutically effective amount of protein or polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30 mg/kg body weight, sometimes about 0.01 to 25 mg/kg body weight, often about 0.1 to 20 mg/kg body weight, and more often about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight. The protein or polypeptide can be administered one time per week for between about 1 to 10 weeks, sometimes between 2 to 8 weeks, often between about 3 to 7 weeks, and more often for about 4, 5, or 6 weeks. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, can include a series of treatments.

For antibodies, a dosage of 0.1 mg/kg of body weight (generally 10 mg/kg to 20 mg/kg) is often utilized. If the antibody is to act in the brain, a dosage of 50 mg/kg to 100 mg/kg is often appropriate.

Generally, partially human antibodies and fully human antibodies have a longer half-life within the human body than other antibodies. Accordingly, lower dosage and less frequent administration is often possible. Modifications such as lipidation can be used to stabilize antibodies and to enhance uptake and tissue penetration (e.g., into the brain). A method for lipidation of antibodies is described by Cruikshank et al. (Cruikshank et al., 1997).

Antibody conjugates can be used for modifying a given biological response, the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a polypeptide such as tumor necrosis factor, alpha-interferon, beta-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors. Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980.

For compounds, exemplary doses include milligram or microgram amounts of the compound per kilogram of subject or sample weight, for example, about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is understood that appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. When one or more of these small molecules is to be administered to an animal (e.g., a human) in order to modulate expression or activity of a polypeptide or nucleic acid described herein, a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

With regard to nucleic acid formulations, gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Pat. No.
5,328,470) or by stereotactic injection (Chen et al., 1994). Pharmaceutical preparations of gene therapy vectors can include a gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells (e.g., retroviral vectors) the pharmaceutical preparation can include one or more cells which produce the gene delivery system. Examples of gene delivery vectors are described herein.

Therapeutic Methods A therapeutic formulation described above can be administered to a subject in need of a therapeutic for treating colorectal cancer. Therapeutic formulations can be administered by any of the paths described herein. With regard to both prophylactic and therapeutic methods of treatment, such treatments may be specifically tailored or modified, based on knowledge obtained from pharmacogenomic analyses described herein.

A treatment is the application or administration of a therapeutic formulation to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect colorectal cancer, symptoms of colorectal cancer or a predisposition towards colorectal cancer. A
therapeutic formulation includes small molecules, peptides, antibodies, ribozymes and antisense oligonucleotides. Administration of a therapeutic fortnulation can occur prior to the manifestation of symptoms characteristic of colorectal cancer, such that the cancer is prevented or delayed in its progression. The appropriate therapeutic composition can be determined based on screening assays described herein.

As discussed, successful treatment of colorectal cancer can be brought about by techniques that serve to agonize target molecule expression or function, or alternatively, antagonize target molecule expression or function. These techniques include administration of modulators that include, but are not limited to, small organic or inorganic molecules; antibodies (including, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and FAb, F(ab')2 and FAb expression library fragments, scFV molecules, and epitope-binding fragments thereof); and peptides, phosphopeptides, or polypeptides.

Further, antisense and ribozyme molecules that inhibit.expression of the target gene can also be used to reduce the level of target gene expression, thus effectively reducing the level of target gene activity.
Still further, triple helix molecules can be utilized in reducing the level of target gene activity.
Antisense, ribozyme and triple helix molecules are discussed above. It is possible that the use of antisense, ribozyme, and/or triple helix molecules to reduce or inhibit mutant gene expression can also reduce or inhibit the transcription (triple helix) and/or translation (antisense, ribozyme) of mRNA
produced by normal target gene alleles, such that the concentration of normal target gene product present can be lower than is necessary for a normal phenotype. In such cases, nucleic acid molecules that encode and express target gene polypeptides exhibiting normal target gene activity can be introduced into cells via gene therapy method. Alternatively, in instances in that the target gene encodes an extracellular polypeptide, it can be preferable to co-administer normal target gene polypeptide into the cell or tissue in order to maintain the requisite level of cellular or tissue target gene activity.
Another method by which nucleic acid molecules may be utilized in treating or preventing colorectal cancer is use of aptamer molecules specific for target molecules. Aptamers are nucleic acid molecules having a tertiary structure which permits them to specifically bind to ligands (Osborne et al., 1997;
Patel, 1997).

Yet another method of utilizing nucleic acid molecules for colorectal cancer treatment is gene therapy, which can also be referred to as allele therapy. The invention thus includes a gene therapy method for treating colorectal cancer in a subject, which includes contacting one or more cells in the subject or from the subject with a nucleic acid having a first nucleotide sequence.
Genomic DNA in the subject includes a second nucleotide sequence having one or more SNPs associated with colorectal cancer. The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence comprises fewer SNPs associated with colorectal cancer than the second nucleotide sequence. The first nucleotide sequence may comprise a gene sequence that encodes a full-length polypeptide or a fragment thereof. The subject is often a human. Allele therapy methods often are utilized in conjunction with a method of first determining whether a subject has genomic DNA that includes SNPs associated with colorectal cancer.

Another allele therapy is a method which comprises contacting one or more cells in the subject or from the subject with a polypeptide encoded by a nucleic acid having a first nucleotide sequence. Genomic DNA in the subject includes a second nucleotide sequence having one or more SNPs associated with colorectal cancer. The first and second nucleotide sequences typically are substantially identical to one another, and the first nucleotide sequence includes fewer SNPs associated with colorectal cancer than the second nucleotide sequence. The first nucleotide sequence may include a gene sequence that encodes a full-length polypeptide or a fragment thereof. The subject is usually a human.

For antibody-based therapies, antibodies can be generated that are both specific for target molecules and that reduce target molecule activity. Such antibodies may be administered in instances where antagonizing a target molecule function is appropriate for the treatment of colorectal cancer.

In circumstances where stimulating antibody production in an animal or a human subject by injection with a target molecule is harmful to the subject, it is possible to generate an immune response against the target molecule by use of anti-idiotypic antibodies (Herlyn and Birebent, 1999; Bhattacharya-Chatterjee and Foon, 1998). Introducing an anti-idiotypic antibody to a mammal or human subject often stimulates production of anti-anti-idiotypic antibodies, which typically are specific to the target molecule. Vaccines directed to colorectal cancer also may be generated in this fashion.

In instances where the target molecule is intracellular and whole antibodies are used, internalizing antibodies often are utilized. Lipofectin or liposomes can be used to deliver the antibody or a fragment of the Fab region that binds to the target antigen into cells. Where fragments of the antibody are used, the smallest inhibitory fragment that binds to the target antigen often is utilized. For example, peptides having an amino acid sequence corresponding to the Fv region of the antibody can be used.
Alternatively, single chain neutralizing antibodies that bind to intracellular target antigens can also be administered. Such single chain antibodies can be administered, for example, by expressing nucleotide sequences encoding single-chain antibodies within the target cell population (Marasco et al., 1993).
Modulators can be administered to a patient at therapeutically effective doses to treat colorectal cancer.
A therapeutically effective dose refers to an amount of the modulator sufficient to result in amelioration of symptoms of colorectal cancer. Toxicity and therapeutic efficacy of modulators can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the EDSo (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Modulators that exhibit large therapeutic indices often are utilized. While modulators that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such molecules to the site of affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects.

Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds typically lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. The therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

Another example of effective dose determination for an individual is the ability to directly assay levels of "free" and "bound" compound in the serum of the test subject. Such assays may utilize antibody mimics and/or "biosensors" that have been created through molecular imprinting techniques. Molecules that modulate target molecule activity are used as a template, or "imprinting molecule", to spatially organize polymerizable monomers prior to their polymerization with catalytic reagents. The subsequent removal of the imprinted molecule leaves a polymer matrix which contains a repeated "negative image"
of the compound and is able to selectively rebind the molecule under biological assay conditions. A
detailed review of this technique can be seen in Ansell et al. (Ansell et al., 1996). Such "imprinted"

affmity matrixes are amenable to ligand-binding assays, whereby the immobilized monoclonal antibody component is replaced by an appropriately imprinted matrix. An example of the use of such matrixes in this way can be seen in Vlatakis, et al. (Vlatakis et al., 1993). Through the use of isotope-labeling, the "free" concentration of compound which modulates target molecule expression or activity readily can be monitored and used in calculations of IC5o. Such "imprinted" affinity matrixes can also be designed to include fluorescent groups whose photon-emitting properties measurably change upon local and selective binding of target compound. These changes readily can be assayed in real time using appropriate fiberoptic devices, in turn allowing the dose in a test subject to be quickly optimized based on its individual IC50=

The examples set forth below are intended to illustrate but not limit the invention.

Genomic DNA samples from patients aged 25-74 and patients with both familial and sporadic CRC
with family and unrelated ethnically matched controls were studied. We identified CRC-associated alleles by measuring 99,632 single nucleotide polymorphisms in peripheral blood DNA from 2475 subjects (1234 cases with colorectal cancer and 1241 age matched individuals undiseased at the time of testing), and validating the identified CRC-associated alleles by using peripheral blood DNA from a second, different, group of 2194 subjects (1139 cases with colorectal cancer and 1055 age matched individuals undiseased at the time of testing). Patients with clinically documented well characterized inherited colorectal cancer syndromes such as Familial Adenomatous Polyposis (FAP) or Hereditary Non Polyposis Colorectal Cancer were excluded from our analysis. Single nucleotide polymorphisms were selected to maximize measurement of genomic variability by choosing these markers that were in the greatest degree of linkage disequilibrium with neighboring SNPs. This was determined by calculating correlation coefficients (r2) with successive neighboring SNPs at each site of polymorphism until an arbitrary cut off of 0.8 was observed. Marker SNPs selected for measurement were in linkage disequilibrium with a maximal number of adjacent SNPs, thus providing an economical method for measuring diversity over a large portion of the genome.

Single Nucleotide Polymorphisms selected for study were derived from the International Haplotype Mapping Project (http://www.hapmap.org) August 2004 release, information about which is available from the National Institutes of Health, National Institutes of Health (NIH;
http://www.nih.gov/), 9000 Rockville Pike, Bethesda, Maryland 20892. The SNPs were analyzed on DNA from our control and study population using either the MIP platform (http://www.affymetrix.com, Affymetrix, Inc., 3380 Central Expressway, Santa Clara, CA 95051), or the Affymetrix platform (http://www.affymetrix.com, Affymetrix, Inc., 3380 Central Expressway, Santa Clara, CA 95051). The SNPs for the MIP platform were selected to include most SNPs that would alter the coding sequence of a protein product. The SNPs for the Affymetrix platform were selected as to cover the entire genome, but the SNPs were preferentially selected in genic regions present on Xbal or HindIIl restriction fragments varying in length from about 20 base pairs to about 1000 base pairs. Data was stored and organized using the Nanuq informatics environment of the McGill University and Genome Quebec Innovation Centre (http://www.genomequebec.mcgill.ca/; McGill University and Genome Qu6bec Innovation Centre, 740, Docteur Penfield Avenue, Montreal, Quebec H3A lA4). Allele frequencies found within DNA from patients with colorectal cancer and those without this disease were compared using the univariate Mantel-Haenszel Chi-Square statistic.

The inventors of the present invention have discovered single base pair polymorphisms that are present in a highly significant percentage of the genetic DNA of individuals affected with colorectal cancer while only present in a smaller percentage of individuals who are not known to be affected by the disease.
Example 1 For individuals with colon cancer, the distribution of polymorphic alleles at position 20900501 of chromosome 1, found within the EIF4G3 gene, was different from those without colon cancer with a permuted p-value of 0.0037 (Table 1). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the C allele (designated in Table 1 as allele B=2) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.169 and is reported in Table 1. These data further suggest that this marker, located within the EIF4G3 gene, is associated with colon cancer risk and that the C allele at position 20900501 of chromosome 1 is associated with an increased risk of developing colon cancer.

Table 1 rs no. 2320590 Chromosome; Position 1; 20900501 Gene Name EIF4G3 SEQ ID NO; Position 606; 222293 Genotype; Pheno e n=C; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 2 0.0037 0.168245 299 493 169 1.169 Table lA indicates SNPs found to be in strong linkage disequilibrium with rs2320590. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 1 A Linked SNPs SNP r2 Position on chrl SEQ ID NO
rs951805 0.627 20805662 1 rs710311 0.702 20807307 2 rs1888759 0.871 20810473 3 rs12123092 0.697 20812307 4 rs12121807 0.702 20814435 5 rs10916859 0.702 20833262 6 rs7548269 0.627 20834778 7 rs7548649 0.702 20835387 8 rs3736880 0.702 20843033 9 rs651538 0.902 20843172 10 rs589755 0.896 20845152 11 rs12123093 0.603 20859722 12 rs3856173 0.676 20860139 13 rs4233274 0.966 20866984 14 rs1152999 0.57 20868329 15 rs1152998 0.752 20869596 16 rs3125161 0.729 20871652 17 rs3121071 0.551 20873726 18 rs7520481 0.724 20885691 19 rs935918 0.649 20890966 20 rs10753507 0.867 20897686 21 rs4654873 0.603 20897690 22 rs10799665 0.663 20897946 23 rs2320590 - 20900501 24 rs4654874 0.933 20901973 25 rs4654875 0.555 20910482 26 rs4654724 0.651 20922516 27 rs2305463 0.868 20925487 28 rs7543140 0.605 20925556 29 rs4654880 0.745 20931914 30 rs10916885 0.925 20934009 31 rs6695218 0.539 20935818 32 rs7519685 0.651 20937929 33 rs2167811 0.646 20939816 34 rs3890762 0.899 20943571 35 rs10737452 0.632 20945070 36 rs10916891 0.551 20945280 37 rs4654725 0.651 20945717 38 rs4654726 0.729 20949204 39 rs17449966 0.629 20949302 40 rs7545133 0.729 20951449 41 rs4654881 0.934 20955075 42 rs2290381 0.651 20958577 43 rs4654883 0.895 20959014 44 rs4654727 0.729 20960041 45 rs2275468 0.729 20965681 46 rs6704421 0.902 20965980 47 rs17410008 0.651 20966007 48 rs4654729 0.934 20969559 49 rs3767247 0.651 20972644 50 rs4654887 0.729 20980229 51 rs10916900 0.934 20984365 52 rs6699704 0.551 20986738 53 rs10916903 0.651 20993250 54 rs11805006 0.934 20994909 55 rs6692677 0.934 20997023 56 rs17450586 0.565 20999899 57 rs12407731 0.934 21000095 58 rs10916906 0.643 21000981 59 rs6698440 0.9 21004018 60 rs10916907 0.9 21006394 61 rs10442633 0.9 21010403 62 rs12133780 0.694 21016114 63 rs3767248 0.694 21022160 64 rs6700459 0.617 21024702 65 rs12137408 0.9 21028251 66 rs6697555 0.694 21033244 67 rs10916911 0.9 21035367 68 rs6697284 0.9 21040905 69 rs2271115 0.694 21041170 70 rs4654893 0.551 21050902 71 rs12021529 0.551 21051467 72 rs7540023 0.571 21055398 73 rs10916919 0.566 21062830 74 rs10799677 0.517 21063762 75 rs10799678 0.9 21068091 76 rs12123300 0.575 21068874 77 rs2874367 0.9 21069797 78 rs906254 0.551 21070066 79 rs11302414 0.664 21072609 80 rs12130664 0.617 21078118 81 rs6661116 0.694 21082461 82 rs12070677 0.898 21082628 83 rs6681064 0.694 21084950 84 rs6426658 0.617 21106482 85 rs6685914 0.545 21107684 86 rs6684976 0.694 21112807 87 rs6703227 0.694 21120116 88 rs964466 0.565 21120469 89 rs10493006 0.617 21121210 90 rs6426665 0.9 21127511 91 rs10916927 0.617 21131101 92 rs1354792 0.9 21137181 93 rs12567861 0.551 21140439 94 rs10916930 0.559 21140663 95 rs6426667 0.897 21141522 96 rs6426668 0.694 21141902 97 rs6692244 0.694 21142192 98 rs7521711 0.9 21145524 99 rs1567128 0.512 21149959 100 Example 2 For individuals with colon cancer, the distribution of polyrnorphic alleles at position 54538208 of chromosome 1, found within the SSBP3 gene, was different from those without colon cancer with a permuted p-value of 0.0044 (Table 2). The maximum of the dominant, recessive, and Armitage trend test statistics associated with canying the C allele (designated in Table 2 as allele B=2) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.32 and is reported in Table 2. These data further suggest that this marker, located within the SSBP3 gene, is associated with colon cancer risk and that the C allele at position 54538208 of chromosome 1 is associated with an increased risk of developing colon cancer.

Table 2 rs no. 10489565 Chromosome; Position 1; 54538208 Gene Name SSBP3 SEQ ID NO; Position 607; 45710 Genotype; Pheno e n=C; increased risk Case Flag Allele B Permuted p-Value Hardy-Weinberg AA AB BB Odds Ratio 0 2 0.0044 0.592877 725 230 21 1.32 Table 2A indicates SNPs found to be in strong linkage disequilibrium with rs10489565. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 2A Linked SNPs SNP r2 Position on chrl SEQ ID NO
rs4601533 0.929 54531998 101 rs10489565 - 54538208 102 rs12024740 0.586 54548927 103 rs2073108 0.656 54551090 104 rs12029610 0.639 54556623 105 rs3795357 0.656 54557621 106 rs12022116 0.635 54561302 107 rs12043222 0.656 54561394 108 rs2297573 0.656 54562638 109 rs4141420 0.591 54563585 110 rs12045400 0.656 54563831 111 Example 3 For individuals with colon cancer, the distribution of polymorphic alleles at position 107056364 of chromosome 1, found within the gene, was different from those without colon cancer with a permuted p-value of 0.002 (Table 3). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the A allele (designated in Table 3 as allele B=1) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.476 and is reported in Table 3. These data further suggest that this marker, located within the gene, is associated with colon cancer risk and that the A

allele at position 107056364 of chromosome 1 is associated with an increased risk of developing colon cancer.

Table 3 rs no. 2049064 Chromosome; Position 1; 107056364 Gene Name SEQ ID NO; Position Genotype; Pheno e n=A; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 1 0.002 0.219665 748 126 2 1.476 Table 3A indicates SNPs found to be in strong linkage disequilibrium with rs2049064. To generate this list, correlation coefficients (r 2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 3A Linked SNPs SNP r2 Position on chrl SEQ ID NO
rs11184922 0.502 106818235 112 rs7530540 0.61 106828844 113 rs4914979 0.61 106830088 114 rs10430081 0.568 106891798 115 rs7527883 0.688 106912949 116 rs12066688 0.688 106928115 117 rs7545951 0.574 106930964 118 rs17017475 0.688 106971827 119 rs17017532 0.935 106998017 120 rs17017567 0.932 107004258 121 rs12085613 0.932 107006719 122 rs12078403 0.935 107010986 123 rs12409858 0.935 107011275 124 rs11184981 0.873 107011305 125 rs12407314 0.935 107011409 126 rs12406199 0.932 107011554 127 rs12407335 0.935 107011627 128 rs12410591 0.932 107012941 129 rs10494050 0.935 107014445 130 rs12079669 0.928 107017707 131 rs10494052 0.932 107021830 132 rs17017658 0.935 107024684 133 rs17492154 0.63 107025142 134 rs2139462 0.935 107033827 135 rs17017694 0.932 107034845 136 rs17017723 1.0 107044596 137 rs17017736 1.0 107047341 138 rs12097821 1.0 107048343 139 rs955988 1.0 107052637 140 rs1519889 1.0 107054139 141 rs1519887 1.0 107056341 142 rs2049064 - 107056364 143 rs1519874 0.688 107080550 144 rs2030341 0.688 107081508 145 rs908953 0.734 107086826 146 rs10881449 0.688 107088101 147 rs1607635 0.63 107091984 148 rs1156426 0.688 107092704 149 rs7530116 0.688 107093768 150 rs1519875 0.688 107096669 151 rs1519876 0.672 107098220 152 rs10881450 0.688 107100885 153 rs2102909 0.688 107103052 154 rs10465780 0.672 107115313 155 rs11184996 0.688 107115334 156 Example 4 For individuals with colon cancer, the distribution of polymorphic alleles at position 114975727 of chromosome 1, found within the D1S155E gene, was different from those without colon cancer with a permuted p-value of 0.0067 (Table 4). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the G allele (designated in Table 4 as allele B=3) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.198 and is reported in Table 4. These data further suggest that this marker, located within the D1S155E gene, is associated with colon cancer risk and that the G allele at position 114975727 of chromosome 1 is associated with an increased risk of developing colon cancer.

Table 4 rs no. 10489525 Chromosome; Position 1; 114975727 Gene Name D 1 S 155E
SEQ ID NO; Position 608; 36894 Genotype; Pheno e n=G; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 3 0.0067 0.0740689 107 397 479 1.198 Table 4A indicates SNPs found to be in strong linkage disequilibrium with rs10489525. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 4A Linked SNPs SNP r2 Position on chrl SEQ ID NO
rs10489525 - 114975727 157 Example 5 For individuals with colon cancer, the distribution of polymorphic alleles at position 49189474 of chromosome 2, found within the FSHR gene, was different from those without colon cancer with a permuted p-value of 0.0075 (Table 5). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the G allele (designated in Table 5 as allele B=3) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.222 and is reported in Table 5. These data further suggest that this marker, located within the FSHR gene, is associated with colon cancer risk and that the G allele at position 49189474 of chromosome 2 is associated with an increased risk of developing colon cancer.

Table 5 rs no. 1504175 Chromosome; Position 2; 49189474 Gene Name FSHR
SEQ ID NO; Position 609; 103808 Geno e; Pheno e n=G; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 3 0.0075 0.311075 320 435 170 1.222 Table 5A indicates SNPs found to be in strong linkage disequilibrium with rs 1504175. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 5A Linked SNPs SNP r2 Position on chr2 SEQ ID NO
rs9807991 0.693 49163446 158 rs10171892 0.579 49169518 159 rs10865238 0.626 49180455 160 rs12614817. 0.776 49183068 161 rs3850344 0.731 49184463 162 rs6716567 1.0 49185265 163 rs11125197 1.0 49186995 164 rs13004879 0.688 49187513 165 rs3913665 0.757 49187893 166 rs1504175 - 49189474 167 rs1504177 0.737 49189694 168 rs2134811 0.757 49190619 169 rs13032266 1.0 49191171 170 rs1504188 0.74 49191484 171 rs1504190 0.737 49192006 172 rs2091786 0.565 49195881 173 rs1394207 0.572 49199434 174 rs4420736 0.565 49199611 175 rs11676909 0.581 49203878 176 rs12473815 0.628 49204013 177 rs1882560 0.565 49205020 178 rs12620805 0.598 49205539 179 rs6716923 0.552 49227109 180 rs976230 0.552 49239677 181 rs11898430 0.539 49239769 182 rs974896 0.568 49242500 183 rs974897 0.552 49242583 184 rs4510264 0.552 49244528 185 rs9309159 0.502 49253703 186 rs1032838 0.556 49311997 187 rs11125217 0.556 49319087 188 rs11685850 0.556 49329514 189 rs9309160 0.556 49329682 190 rs6720857 0.53 49332061 191 rs4564810 0.53 49332761 192 rs11125222 0.524 49335916 193 Example 6 For individuals with colon cancer, the distribution of polymorphic alleles at position 25244762 of chromosome 3, found within the LOC442077 gene, was different from those without colon cancer with a permuted p-value of 0.0048 (Table 6). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the A allele (designated in Table 6 as allele B=1) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.35 and is reported in Table 6. These data further suggest that this marker, located within the LOC442077 gene, is associated with colon cancer risk and that the A allele at position 25244762 of chromosome 3 is associated with an increased risk of developing colon cancer.

Table 6 rs no. 10510558 Chromosome; Position 3; 25244762 Gene Name LOC442077 SEQ ID NO; Position 610; 53870 Genotype; Pheno e n=A; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 1 0.0048 1 20 243 715 1.35 Table 6A indicates SNPs found to be in strong linkage disequilibrium with rs10510558. To generate this list, correlation coefficients (rz) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 6A Linked SNPs SNP r 2 Position on chr3 SEQ ID NO
rs17517931 0.914 25184366 194 rs13068891 0.853 25188663 195 rs13061437 0.924 25194200 196 rs17578042 0.929 25205423 197 rs17578259 0.929 25207827 198 rs13100362 0.872 25211158 199 rs2068130 0.818 25211837 200 rs1561115 0.932 25235457 201 rs17015971 0.932 25238040 202 rs13096074 0.844 25239011 203 rs17015978 1.0 25239845 204 rs7432016 1.0 25243914 205 rs10510558 - 25244762 206 rs10510559 1.0 25244932 207 rs10510560 1.0 25245547 208 rs13092896 0.799 25250478 209 rs7427426 1.0 25264520 210 rs1601161 1.0 25265009 211 rs1992060 0.919 25269521 212 rs1992059 0.932 25273091 213 rs13082318 0.932 25273425 214 rs13087573 0.932 25274083 215 rs17016060 0.932 25275052 216 rs13074533 0.932 25277488 217 rs10510561 0.932 25279386 218 rs17016078 0.932 25280012 219 rs13093059 0.932 25280571 220 rs13068143 0.932 25283486 221 rs13091754 0.932 25283965 222 rs17016117 0.932 25284812 223 rs17016120 0.932 25285067 224 rs13059799 0.932 25287098 225 rs13082440 0.928 25287161 226 rs17016133 0.932 25288171 227 rs13084418 0.932 25291318 228 rs13084608 0.932 25291410 229 rs17016141 0.861 25295964 230 rs1436239 0.861 25300483 231 Example 7 For individuals with colon cancer, the distribution of polymorphic alleles at position 156010845 of chromosome 4, found within the LRAT gene, was different from those without colon cancer with a permuted p-value of 0.0063 (Table 7). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the T allele (designated in Table 7 as allele B=4) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.407 and is reported in Table 7. These data further suggest that this marker, located within the LRAT gene, is associated with colon cancer risk and that the T allele at position 156010845 of chromosome 4 is associated with an increased risk of developing colon cancer.

Table 7 rs no. 10517602 Chromosome; Position 4; 156010845 Gene Name LRAT
SEQ ID NO; Position 611;
Geno e; Pheno e n=T; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 4 0.0063 0.222909 816 134 2 1.407 Table 7A indicates SNPs found to be in strong linkage disequilibrium with rs10517602. To generate this list, correlation coefficients (rz) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 7A Linked SNPs SNP r2 Position on chr4 SEQ ID NO
rs17031951 1.0 156007562 232 rs17031954 1.0 156008015 233 rs17031957 1.0 156009501 234 rs10517602 - 156010845 235 rs12501328 1.0 156019936 236 rs1876031 1.0 156020341 237 rs3775785 1.0 156027459 238 rs12507608 1.0 156029231 239 rs17032000 1.0 156030563 240 rs1392546 1.0 156032538 241 rs1500372 1.0 156033905 242 Example 8 For individuals with colon cancer, the distribution of polymorphic alleles at position 83088471 of chromosome 6, found within the TPBG gene, was different from those without colon cancer with a permuted p-value of 0.0016 (Table 8). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the T allele (designated in Table 8 as allele B=4) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.28 and is reported in Table 8. These data further suggest that this marker, located within the TPBG gene, is associated with colon cancer risk and that the T allele at position 83088471 of chromosome 6 is associated with an increased risk of developing colon cancer.

Table 8 rs no. 508106 Chromosome; Position 6; 83088471 Gene Name TPBG
SEQ ID NO; Position 612;
Genotype; Pheno e n=T; increased risk Case Flag Allele B Permuted p-Value Hardy-Weinberg AA AB BB Odds Ratio 0 4 0.0016 0.268338 496 377 85 1.28 Table 8A indicates SNPs found to be in strong linkage disequilibrium with rs508106. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 8A Linked SNPs SNP r2 Position on chr6 SEQ ID NO
rs2323642 0.644 82950808 243 rs540814 0.544 83037702 244 rs2753211 0.675 83052756 245 rs2753212 0.69 83052893 246 rs9344267 0.792 83059529 247 rs62953 0.763 83059811 248 rs529833 0.748 83063355 249 rs544734 0.958 83065585 250 rs554594 0.958 83065715 251 rs511002 1.0 83066965 252 rs507500 0.919 83067321 253 rs532219 1.0 83079412 254 rs577767 0.958 83086171 255 rs526833 0.957 83086772 256 rs7756828 1.0 83087733 257 rs508106 - 83088471 258 rs555844 0.919 83089659 259 rs1923137 1.0 83092525 260 rs1923138 0.957 83092537 261 rs723142 1.0 83094274 262 rs2180742 1.0 83094499 263 rs1547614 0.958 83094576 264 rs2145368 1.0 83095347 265 rs2180743 1.0 83095565 266 rs7762072 0.955 83095939 267 rs13191698 0.919 83096974 268 rs13207433 0.958 83097004 269 rs1321622 0.876 83097222 270 rs9353066 0.919 83098262 271 rs6907015 0.958 83098329 272 rs6930014 0.958 83098352 273 rs9353067 0.872 83100260 274 rs9353068 1.0 83101000 275 rs2024996 0.876 83103870 276 rs796398 0.958 83113039 277 rs770904 0.913 83114887 278 rs770897 0.782 83120523 279 rs770898 0.75 83122607 280 rs770895 0.773 83127291 281 rs1570140 0.754 83129590 282 rs770911 0.754 83131084 283 rs1275806 0.658 83137358 284 rs770906 0.517 83140060 285 rs932614 0.517 83146661 286 rs9344274 0.508 83147795 287 rs1951006 0.52 83150543 288 rs9449462 0.507 83153296 289 rs9361914 0.505 83155501 290 rs714133 0.52 83162032 291 rs1998204 0.508 83163350 292 rs1853143 0.508 83165082 293 rs4706945 0.52 83165771 294 rs9449469 0.52 83167427 295 rs9449470 0.544 83167802 296 rs4706948 0.505 83168404 297 rs2875128 0.532 83169297 298 rs6912008 0.508 83169493 299 rs9449475 0.623 83170215 300 rs967730 0.553 83170490 301 rs967731 0.544 83170598 302 rs9361923 0.508 83172329 303 Example 9 For individuals with colon cancer, the distribution of polymorphic alleles at position 129960703 of chromosome 6, found within the ARHGAP 18 gene, was different from those without colon cancer with a permuted p-value of 0.0007 (Table 9). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the C allele (designated in Table 9 as allele B=2) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.367 and is reported in Table 9. These data further suggest that this marker, located within the ARHGAP18 gene, is associated with colon cancer risk and that the C allele at position 129960703 of chromosome 6 is associated with an increased risk of developing colon cancer.

Table 9 rs no. 10499162 Chromosome; Position 6; 129960703 Gene Name ARHGAP18 SEQ ID NO; Position 613; 112361 Genotype; Pheno e n=C; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 2 0.0007 0.169459 748 215 9 1.367 Table 9A indicates SNPs found to be in strong linkage disequilibrium with rs10499162. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 9A Linked SNPs SNP r2 Position on chr6 SEQ ID NO
rs10499162 - 129960703 304 rs3829756 1.0 129968495 305 rs9375636 0.635 129970245 306 Example 10 For individuals with colon cancer, the distribution of polymorphic alleles at position 11585877 of chromosome 7, found within the KIAA0960 gene, was different from those without colon cancer with a permuted p-value of 0.006 (Table 10). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the G allele (designated in Table 10 as allele B=3) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.192 and is reported in Table 10. These data further suggest that this marker, located within the KIAA0960 gene, is associated with colon cancer risk and that the G allele at position 11585877 of chromosome 7 is associated with an increased risk of developing colon cancer.

Table 10 rs no. 2355084 Chromosome; Position 7; 11585877 Gene Name KIAA0960 SEQ ID NO; Position 614; 339055 Genotype; Pheno e n=G; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 3 0.006 0.351002 544 380 56 1.192 Table 10A indicates SNPs found to be in strong linkage disequilibrium with rs2355084. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table l0A Linked SNPs SNP rz Position on chr7 SEQ ID NO
rs2355084 - 11585877 307 Example 11 For individuals with colon cancer, the distribution of polymorphic alleles at position 81559837 of chromosome 7, found within the CACNA2D1 gene, was different from those without colon cancer with a permuted p-value of 0.0055 (Table 11). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the C allele (designated in Table 11 as allele B=2) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.485 and is reported in Table 11. These data further suggest that this marker, located within the CACNA2D1 gene, is associated with colon cancer risk and that the C allele at position 81559837 of chromosome 7 is associated with an increased risk of developing colon cancer.

Table 11 rs no. 10280428 Chromosome; Position 7; 81559837 Gene Name CACNA2D 1 SEQ ID NO; Position 615; 157620 Genotype; Pheno e n=C; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 2 0.0055 0.00292766 884 85 8 1.485 Table 11A indicates SNPs found to be in strong linkage disequilibrium with rs10280428. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 11A Linked SNPs SNP rZ Position on chr7 SEQ ID NO
rs11768310 0.88 81554149 308 rs10279911 0.915 81559478 309 rs10280428 - 81559837 310 rs11763784 1.0 81641687 311 rs11768220 0.901 81648931 312 rs11770457 0.88 81654315 313 Example 12 For individuals with colon cancer, the distribution of polymorphic alleles at position 144767960 of chromosome 7, found within the gene, was different from those without colon cancer with a permuted p-value of 0.0069 (Table 12). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the T allele (designated in Table 12 as allele B=4) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.001 and is reported in Table 12. These data further suggest that this marker, located within the gene, is associated with colon cancer risk and that the T allele at position 144767960 of chromosome 7 is associated with an increased risk of developing colon cancer.

Table 12 rs no. 850470 Chromosome; Position 7; 144767960 Gene Name SEQ ID NO; Position Geno e; Pheno e n=T; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 4 0.0069 0.000710347 96 338 505 1.001 Table 12A indicates SNPs found to be in strong linkage disequilibrium with rs850470. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 12A Linked SNPs SNP r2 Position on chr7 SEQ ID NO
rs12532655 0.538 144628286 314 rs12534416 0.538 144628318 315 rs7805406 0.546 144628632 316 rs12533991 0.538 144629754 317 rs12533483 0.538 144629965 318 rs6968614 0.574 144630098 319 rs12374872 0.574 144635813 320 rs6968911 0.582 144643683 321 rs7784182 0.574 144645286 322 rs10280300 0.574 144646697 323 rs6964491 0.7 144669590 324 rs6951319 0.695 144669600 325 rs1357620 0.701 144671926 326 rs12531013 0.748 144672558 327 rs17169751 0.695 144676393 328 rs1357624 0.701 144678594 329 rs1357623 0.701 144678612 330 rs17169752 0.701 144680315 331 rs17169763 0.885 144718311 332 rs17169765 0.913 144720727 333 rs850456 0.72 144733992 334 rs850455 0.884 144734180 335 rs850454 0.884 144734239 336 rs850452 0.885 144734742 337 rs850505 0.85 144744457 338 rs850500 0.956 144745774 339 rs850499 0.885 144745875 340 rs850493 0.957 144751586 341 rs850492 0.958 144752182 342 rs850491 0.961 144752705 343 rs850490 0.957 144753415 344 rs850489 0.961 144753565 345 rs850487 0.957 144755233 346 rs850486 0.961 144755604 347 rs850485 0.961 144755775 348 rs850483 0.961 144756961 349 rs850482 0.961 144757255 350 rs850480 1.0 144759437 351 rs850478 0.961 144760563 352 rs850476 0.961 144761726 353 rs850474 0.96 144766026 354 rs850472 0.961 144766794 355 rs850470 - 144767960 356 rs850468 0.693 144768118 357 rs850467 1.0 144768579 358 rs850466 1.0 144768715 359 rs850462 0.854 144770877 360 rs850461 0.85 144770905 361 rs850458 0.844 144771574 362 rs850457 0.854 144771653 363 rs860333 0.854 144771867 364 rs10246840 0.854 144774486 365 rs6952320 0.847 144774883 366 rs1079789 0.852 144776678 367 rs10952623 0.857 144777538 368 rs1468582 0.857 144778707 369 rs2372057 0.851 144781332 370 rs10952624 0.857 144781771 371 rs733171 0.857 144782495 372 rs10952625 0.857 144783026 373 rs12667814 0.618 144783666 374 rs6976909 0.857 144784599 375 rs2079830 0.849 144785299 376 rs12154287 0.533 144788902 377 rs1990347 0.857 144791211 378 rs10267840 0.857 144793063 379 rs10808035 0.857 144796105 380 rs11763425 0.884 144799583 381 rs2191275 0.887 144799675 382 rs12535408 0.856 144800213 383 rs6961951 0.857 144800438 384 rs6962101 0.857 144800519 385 rs6979892 0.805 144800830 386 rs12703731 0.58 144801300 387 rs6951436 0.857 144802085 388 rs11761238 0.821 144802576 389 rs10228710 0.857 144803188 390 rs7810370 0.857 144803650 391 rs6464691 0.857 144804012 392 rs6962254 0.857 144804167 393 rs2888244 0.854 144805193 394 rs4285408 0.857 144805467 395 rs11764219 0.857 144806025 396 rs6944748 0.857 144806327 397 rs6969500 0.809 144806354 398 rs10952627 0.857 144808010 399 rs6966867 0.857 144810732 400 rs10237200 0.849 144814121 401 rs10266218 0.846 144814527 402 rs850571 0.852 144818301 403 rs850570 0.857 144819907 404 Example 13 For individuals with colon cancer, the distribution of polymorphic alleles at position 149242026 of chromosome 7, found within the gene, was different from those without colon cancer with a permuted p-value of 0.0017 (Table 13). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the G allele (designated in Table 13 as allele B=3) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.399 and is reported in Table 13. These data further suggest that this marker, located within the gene, is associated with colon cancer risk and that the G allele at position 149242026 of chromosome 7 is associated with an increased risk of developing colon cancer.

Table 13 rs no. 3864498 Chromosome; Position 7; 149242026 Gene Name SEQ ID NO; Position Genotype; Pheno e n=G; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 3 0.0017 0.677983 19 209 635 1.399 Table 13A indicates SNPs found to be in strong linkage disequilibrium with rs3864498. To generate this list, correlation coefficients (rz) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 13A Linked SNPs SNP r2 Position on chr7 SEQ ID NO
rs3864498 - 149242026 405 Example 14 For individuals with colon cancer, the distribution of polymorphic alleles at position 4257764 of chromosome 8, found within the CSMDI gene, was different from those without colon cancer with a permuted p-value of 0.0033 (Table 14). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the A allele (designated in Table 14 as allele B=1) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.267 and is reported in Table 14. These data further suggest that this marker, located within the CSMD1 gene, is associated with colon cancer risk and that the A allele at position 4257764 of chromosome 8 is associated with an increased risk of developing colon cancer.

Table 14 rs no. 10503262 Chromosome; Position 8; 4257764 Gene Name CSMD1 SEQ ID NO; Position 616; 581973 Genotype; Pheno e n=A; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 1 0.0033 0.000625158 70 289 548 1.267 Table 14A indicates SNPs found to be in strong linkage disequilibrium with rs10503262. To generate this list, correlation coefficients (rz) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 14A Linked SNPs SNP r2 Position on chr8 SEQ ID NO
rs10089026 0.957 4252805 406 rs10092807 1.0 4257185 407 rs10503262 - 4257764 408 Example 15 For individuals with colon cancer, the distribution of polymorphic alleles at position 55701610 of chromosome 8, found within the RP 1 gene, was different from those without colon cancer with a permuted p-value of 0.0131 (Table 15). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the G allele (designated in Table 15 as allele B=3) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.199 and is reported in Table 15. These data further suggest that this marker, located within the RP1 gene, is associated with colon cancer risk and that the G allele at position 55701610 of chromosome 8 is associated with an increased risk of developing colon cancer.

Table 15 rs no. 444772 Chromosome; Position 8; 55701610 Gene Name RP 1 SEQ ID NO; Position 617; 10431 Genotype; Pheno e n=G; increased risk Case Flag Allele B Permuted p-Value Hardy-Weinberg AA AB BB Odds Ratio 0 3 0.0131 0.943928 103 481 567 1.199 Table 15A indicates SNPs found to be in strong linkage disequilibrium with rs444772. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 15A Linked SNPs SNP r2 Position on chr8 SEQ ID NO
rs421844 0.95 55688038 409 rs435326 0.952 55688723 410 rs396881 0.954 55688788 411 rs446102 0.954 55689106 412 rs702761 1.0 55691506 413 rs145290 1.0 55692165 414 rs428854 1.0 55698923 415 rs429668 1.0 55699691 416 rs444772 - 55701610 417 rs446227 1.0 55704003 418 rs414352 1.0 55704066 419 rs441800 1.0 55704170 420 rs388912 1.0 55714151 421 rs376055 1.0 55718398 422 rs448744 1.0 55720864 423 rs433265 1.0 55724371 424 rs421469 1.0 55724624 425 rs383666 1.0 55725409 426 rs509273 1.0 55729655 427 rs428630 1.0 55732233 428 rs369565 1.0 55734727 429 rs858428 1.0 55734972 430 rs499324 1.0 55735628 431 rs409429 1.0 55735791 432 rs426380 0.909 55736905 433 rs439539 1.0 55738068 434 rs433881 1.0 55740834 435 rs437439 1.0 55741606 436 rs450496 1.0 55742554 437 rs371043 1.0 55752508 438 rs394020 1.0 55760756 439 rs395862 1.0 55761309 440 rs858396 1.0 55776456 441 rs893361 1.0 55783865 442 rs6473950 0.955 55801936 443 rs1437785 0.955 55811566 444 rs7000259 0.955 55821626 445 rs4737673 0.955 55823685 446 rs1509678 0.955 55825618 447 rs2375220 0.955 55845129 448 rs1553764 0.955 55858095 449 rs1498181 0.955 55861650 450 rs1498182 0.866 55870126 451 rs1039842 0.955 55880446 452 rs9298510 0.954 55883850 453 rs1498189 0.802 55886453 454 Example 16 For individuals with colon cancer, the distribution of polymorphic alleles at position 128476625 of chromosome 8, found within the POU5F 1 P 1 gene, was different from those without colon cancer with a permuted p-value of 0.003 (Table 16). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the A allele (designated in Table 16 as allele B=1) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.226 and is reported in Table 16. These data further suggest that this marker, located within the POU5F1P1 gene, is associated with colon cancer risk and that the A allele at position 128476625 of chromosome 8 is associated with an increased risk of developing colon cancer.

Table 16 rs no. 10505477 Chromosome; Position 8; 128476625 Gene Name POU5F1P1 SEQ ID NO; Position 618;
Genotype; Pheno e n=A; increased risk Case Flag Allele B Permuted p-Value Hardy-Weinberg AA AB BB Odds Ratio 0 1 0.003 1 249 492 241 1.226 Table 16A indicates SNPs found to be in strong linkage disequilibrium with rs10505477. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 16A Linked SNPs SNP r2 Position on chr8 SEQ ID NO
rs10505477 - 128476625 455 rs10808556 0.627 128482329 456 rs6983267 0.935 128482487 457 rs10505474 0.632 128486686 458 rs2060776 0.609 128489299 459 rs4871788 0.609 128490967 460 rs7837328 0.609 128492309 461 rs7837626 0.609 128492523 462 rs7837644 0.609 128492580 463 rs871135 0.609 128495575 464 Example 17 For individuals with colon cancer, the distribution of polymorphic alleles at position 110115339 of chromosome 9, found within the gene, was different from those without colon cancer with a permuted p-value of 0.0061 (Table 17). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the A allele (designated in Table 17 as allele B=1) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.288 and is reported in Table 17. These data further suggest that this marker, located within the gene, is associated with colon cancer risk and that the A allele at position 110115339 of chromosome 9 is associated with an increased risk of developing colon cancer.

Table 17 rs no. 10512404 Chromosome; Position 9; 110115339 Gene Name SEQ ID NO; Position Genotype; Pheno e n=A; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 1 0.0061 0.016616 47 278 657 1.288 Table 17A indicates SNPs found to be in strong linkage disequilibrium with rs10512404. To generate this list, correlation coefficients (r 2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 17A Linked SNPs SNP r2 Position on chr9 SEQ ID NO
rs10512404 - 110115339 465 rs10980301 1.0 110130428 466 Example 18 For individuals with colon cancer, the distribution of polymorphic alleles at position 4453422 of chromosome 11, found within the OR52K3P gene, was different from those without colon cancer with a permuted p-value of 0.0079 (Table 18). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the T allele (designated in Table 18 as allele B=4) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.194 and is reported in Table 18. These data further suggest that this marker, located within the OR52K3P gene, is associated with colon cancer risk and that the T allele at position 4453422 of chromosome 11 is associated with an increased risk of developing colon cancer.

Table 18 rs no. 2278170 Chromosome; Position 11; 4453422 Gene Name OR52K3P
SEQ ID NO; Position 619; 808 Genotype; Pheno e n=T; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 4 0.0079 0.0962063 581 441 106 1.194 Table 18A indicates SNPs found to be in strong linkage disequilibrium with rs2278170. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 18A Linked SNPs SNP r2 Position on chrl l SEQ ID NO
rs167948 0.593 4430296 467 rs10836079 0.835 4430392 468 rs191761 0.573 4430569 469 rs7395324 1.0 4434860 470 rs11032345 1.0 4440254 471 rs10836102 1.0 4442501 472 rs11032351 1.0 4443277 473 rs11032354 0.928 4443753 474 rs11032359 0.925 4444427 475 rs11032361 0.929 4444806 476 rs10768026 1.0 4446686 477 rs331502 0.963 4448408 478 rs11032378 0.929 4449042 479 rs11032381 0.929 4449105 480 rs890416 0.929 4449910 481 rs890417 0.927 4450407 482 rs890418 0.929 4450528 483 rs331503 1.0 4451604 484 rs9633905 1.0 4453189 485 rs2278170 - 4453422 486 rs2278171 1.0 4453492 487 rs2278172 0.964 4453537 488 rs2278173 1.0 4453673 489 rs 11032407 1.0 4454017 490 rs9633900 1.0 4454894 491 rs2641405 0.658 4532655 492 rs11032827 0.577 4543829 493 Example 19 For individuals with colon cancer, the distribution of polymorphic alleles at position 115738853 of chromosome 11, found within the gene, was different from those without colon cancer with a permuted p-value of 0.0063 (Table 19). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the A allele (designated in Table 19 as allele B=1) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.225 and is reported in Table 19. These data further suggest that this marker, located within the gene, is associated with colon cancer risk and that the A allele at position 115738853 of chromosome 11 is associated with an increased risk of developing colon cancer.

Table 19 rs no. 572619 Chromosome; Position 11; 115738853 Gene Name SEQ ID NO; Position Genotype; Pheno e n=A; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 1 0.0063 1 137 459 386 1.225 Table 19A indicates SNPs found to be in strong linkage disequilibrium with rs572619. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 19A Linked SNPs SNP r2 Position on chrl I SEQ ID NO
rs572619 - 115738853 494 rs574529 1.0 115739067 495 rs526151 0.595 115741985 496 rs571139 0.925 115742227 497 rs488435 0.603 115742992 498 rs491111 0.929 115743244 499 rs567559 0.662 115744952 500 rs541874 0.646 115745463 501 rs11215905 0.548 115747903 502 Example 20 For individuals with colon cancer, the distribution of polymorphic alleles at position 9814118 of chromosome 12, found within the CD69 gene, was different from those without colon cancer with a permuted p-value of 0.0039 (Table 20). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the A allele (designated in Table 20 as allele B=1) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.25 and is reported in Table 20. These data further suggest that this marker, located within the CD69 gene, is associated with colon cancer risk and that the A allele at position 9814118 of chromosome 12 is associated with an increased risk of developing colon cancer.

Table 20 rs no. 724667 Chromosome; Position 12; 9814118 Gene Name CD69 SEQ ID NO; Position 620;
Genotype; Pheno e n=A; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 1 0.0039 0.0478344 557 300 58 1.25 Table 20A indicates SNPs found to be in strong linkage disequilibrium with rs724667. To generate this list, correlation coefficients (rZ) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 20A Linked SNPs SNP r2 Position on chr12 SEQ ID NO
rs3176789 0.959 9803997 503 rs2071647 1.0 9805272 504 rs3136559 1.0 9807907 505 rs3176776 0.64 9808088 506 rs3176775 0.64 9808349 507 rs3176773 0.597 9809369 508 rs12422685 0.64 9811239 509 rs724668 1.0 9814096 510 rs724667 - 9814118 511 rs724666 1.0 9814380 512 rs1029992 1.0 9817025 513 rs1029991 1.0 9817331 514 rs1029990 1.0 9817664 515 rs10844749 1.0 9817891 516 rs1540356 1.0 9818051 517 rs12582052 1.0 9818837 518 rs1861090 0.921 9820946 519 Example 21 For individuals with colon cancer, the distribution of polymorphic alleles at position 67187174 of chromosome 14, found within the ARG2 gene, was different from those without colon cancer with a permuted p-value of 0.0067 (Table 21). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the C allele (designated in Table 21 as allele B=2) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.478 and is reported in Table 21. These data further suggest that this marker, located within the ARG2 gene, is associated with colon cancer risk and that the C allele at position 67187174 of chromosome 14 is associated with an increased risk of developing colon cancer.

Table 21 rs no. 10483802 Chromosome; Position 14; 67187174 Gene Name ARG2 SEQ ID NO; Position 621; 30766 Genotype; Pheno e n=C; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 2 0.0067 1 910 73 1 1.478 Table 21A indicates SNPs found to be in strong linkage disequilibrium with rs10483802. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 21A Linked SNPs SNP r2 Position on chr14 SEQ ID NO
rs 12436474 1.0 67170429 520 rs10483802 - 67187174 521 rs15493 1.0 67187885 522 rs1804799 1.0 67188117 523 rs17249563 0.743 67194680 524 rs12435927 1.0 67197723 525 rs8013234 1.0 67219687 526 rs3759768 1.0 67233546 527 rs12434923 1.0 67239521 528 rs12435352 1.0 67241643 529 rs2009590 0.589 67257453 530 rs12431676 0.744 67258104 531 rs910315 0.743 67258676 532 rs718213 1.0 67266474 533 rsl 7836863 1.0 67276155 534 Example 22 For individuals with colon cancer, the distribution of polymorphic alleles at position 5830572 of chromosome 16, found within the gene, was different from those without colon cancer with a permuted p-value of 0.003 (Table 22). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the G allele (designated in Table 22 as allele B=3) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.295 and is reported in Table 22. These data further suggest that this marker, located within the gene, is associated with colon cancer risk and that the G allele at position 5830572 of chromosome 16 is associated with an increased risk of developing colon cancer.

Table 22 rs no. 7200548 Chromosome; Position 16; 5830572 Gene Name SEQ ID NO; Position Genotype; Pheno e n=G; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 3 0.003 0.78987 52 356 574 1.295 Table 22A indicates SNPs found to be in strong linkage disequilibrium with rs7200548. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 22A Linked SNPs SNP r2 Position on chr16 SEQ ID NO
rs7187057 0.523 5806139 535 rs7189118 0.513 5806149 536 rs1865820 0.509 5806269 537 rs7189684 0.509 5806460 538 rs7195375 0.509 5807386 539 rs11648254 0.573 5807689 540 rs6500727 0.532 5808267 541 rs2342743 0.507 5808466 542 rs2342745 0.509 5808524 543 rs2342747 0.509 5808701 544 rs2342748 0.509 5808730 545 rs7200468 0.509 5809618 546 rs1550137 0.509 5810450 547 rs2343252* 0.509 5812560 548 rs9930544 0.509 5813426 549 rs4296263 0.532 5819886 550 rs2118014 0.812 5828787 551 rs7200548 - 5830572 552 Example 23 For individuals with colon cancer, the distribution of polymorphic alleles at position 30908917 of chromosome 17, found within the LOC342618 gene, was different from those without colon cancer with a permuted p-value of 0.0027 (Table 23). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the C allele (designated in Table 23 as allele B=2) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.297 and is reported in Table 23. These data further suggest that this marker, located within the LOC342618 gene, is associated with colon cancer risk and that the C allele at position 30908917 of chromosome 17 is associated with an increased risk of developing colon cancer.

Table 23 rs no. 10512472 Chromosome; Position 17; 30908917 Gene Name LOC342618 SEQ ID NO; Position 622; 278 Geno e; Pheno e n=C; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 2 0.0027 0.0657737 675 288 19 1.297 Table 23A indicates SNPs found to be in strong linkage disequilibrium with rs 10512472. To generate this list, correlation coefficients (r2) were calculated between the index SNP
and all neighboring SNPs cited in the January 2006 HapMap data set release. An r 2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 23A Linked SNPs SNP r2 Position on chr17 SEQ ID NO
rs10512472 - 30908917 553 rs12940584 0.536 30912424 554 rs11655098 0.536 30918963 555 rs1037590 1.0 30926748 556 rs11656872 0.536 30962717 557 rs17669281 0.536 30967908 558 rs17606150 0.536 30967921 559 rs16971217 1.0 30968168 560 rs9897552 1.0 30998594 561 rs12943224 0.536 31001651 562 rs11652390 0.536 31006594 563 rs3506 0.536 31011147 564 rs11654542 0.536 31013421 565 rs17670584 0.536 31023017 566 rs17670614 0.536 31023480 567 rs9907772 1.0 31024741 568 rs17676508 0.536 31044721 569 rs17608253 0.536 31050583 570 Example 24 For individuals with colon cancer, the distribution of polymorphic alleles at position 59485642 of chromosome 19, found within the LILRB2 gene, was different from those without colon cancer with a permuted p-value of 0.0071 (Table 24). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the C allele (designated in Table 24 as allele B=2) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.271 and is reported in Table 24. These data further suggest that this marker, located within the LILRB2 gene, is associated with colon cancer risk and that the C allele at position 59485642 of chromosome 19 is associated with an increased risk of developing colon cancer.

Table 24 rsno. 798893 Chromosome; Position 19; 59485642 Gene Name LILRB2 SEQ ID NO; Position 623;
Genotype; Pheno e n=C; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 2 0.0071 0.0528275 601 243 37 1.271 Table 24A indicates SNPs found to be in strong linkage disequilibrium with rs798893. To generate this list, correlation coefficients (r 2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 24A Linked SNPs SNP r2 Position on chr19 SEQ ID NO
rs383369 0.606 59475942 571 rs431420 0.661 59483891 572 rs386000 0.935 59484573 573 rs398217 1.0 59484850 574 rs798887 1.0 59485000 575 rs798893 - 59485642 576 rs416867 0.936 59488442 577 rs384116 1.0 59488531 578 rs103294 1.0 59489660 579 rs410852 0.688 59492183 580 Example 25 For individuals with colon cancer, the distribution of polymorphic alleles at position 19773582 of chromosome 22, found within the LOC402037 gene, was different from those without colon cancer with a permuted p-value of 0.0071 (Table 25). The maximum of the dominant, recessive, and Armitage trend test statistics associated with carrying the G allele (designated in Table 25 as allele B=3) indicates a significant difference between patients with colon cancer relative to patients without colon cancer in the genotype frequencies. The Mantel-Haenszel odds ratio is 1.222 and is reported in Table 25. These data further suggest that this marker, located within the LOC402037 gene, is associated with colon cancer risk and that the G allele at position 19773582 of chromosome 22 is associated with an increased risk of developing colon cancer.

Table 25 rs no. 1431319 Chromosome; Position 22; 19773582 Gene Name LOC402037 SEQ ID NO; Position 624;
Genotype; Pheno e n=G; increased risk Case Flag Allele B Permuted p-Value Hard -Weinber AA AB BB Odds Ratio 0 3 0.0071 0.87086 526 383 72 1.222 Table 25A indicates SNPs found to be in strong linkage disequilibrium with rs431319. To generate this list, correlation coefficients (r2) were calculated between the index SNP and all neighboring SNPs cited in the January 2006 HapMap data set release. An r2 cut off of 0.50 was selected for inclusion as evidence for strong genetic linkage.

Table 25A Linked SNPs SNP r 2 Position on chr22 SEQ ID NO
rs727497 0.598 19751933 581 rs9613607 0.598 19752848 582 rs6417766 0.64 19756298 583 rs6519750 0.566 19756323 584 rs9608684 0.573 19756976 585 rs9613641 0.565 19764380 586 rs444763 0.855 19767837 587 rs415591 0.855 19769591 588 rs399401 0.851 19769618 589 rs933582 0.855 19769950 590 rs11913109 0.519 19771148 591 rs11912450 0.519 19771633 592 rs1210599 1.0 19772588 593 rs444204 1.0 19772956 594 rs365421 1.0 19772978 595 rs367594 1.0 19773492 596 rs431319 - 19773582 597 rs448041 1.0 19773965 598 rs6005623 0.623 19774278 599 rs9306459 0.632 19774574 600 rs9608693 0.601 19774735 601 rs6005625 0.625 19774818 602 rs5997305 0.625 19775246 603 rs1210606 0.885 19776791 604 rs406160 0.963 19778477 605 Another aspect of the invention is a method of diagnosing colorectal cancer in an individual, or determining whether the individual is at altered risk for colorectal cancer, by detecting polymorphism in a subject by treating a tissue sample from the subject with an antibody to a polymorphic genetic variant of the present invention and detecting binding of said antibody. A person of skill in the art would know how to produce such an antibody (see, for instance, Harlow, E. and Lane, eds., 1988, "Antibodies: A
Laboratory Manual", Cold Spring Harbor Press, Cold Spring Harbor). Such antibodies may include, but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab')2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above. The present invention also provides an animal model to study colorectal cancer and susceptibility to colorectal cancer. Such studies can be performed using transgenic animals. For example, one can produce transgenic mice, which contain a specific allelic variant of a containing any of the SNPs disclosed herein. These mice can be created, e.g., by replacing their wild-type gene with an allele containing a SNP disclosed herein, or of the corresponding human gene containing such a SNP.
In a preferred embodiment, the present invention provides a transgenic mammalian animal, said animal having cells incorporating a recombinant expression system adapted to express a gene containing a SNP
disclosed herein (preferably the human gene containing a SNP disclosed herein). Generally, the recombinant expression system will be stably integrated into the genome of the transgenic animal and will thus be heritable so that the offspring of such a transgenic animal may themselves contain the transgene. Transgenic animals can be engineered by introducing the a nucleic acid molecule containing only the coding portion of the gene into the genome of animals of interest, using standard techniques for producing transgenic animals. Animals that can serve as a target for transgenic manipulation include, without limitation, mice, rats, rabbits, guinea pigs, sheep, goats, pigs, and non-human primates, e.g. baboons, chimpanzees and monkeys. Techniques known in the art to introduce a transgene into such animals include pronucleic microinjection (U.S. Pat. No. 4,873,191);
retrovirus-mediated gene transfer into germ lines (e.g. Van der Putten et al. 1985, Proc. Nati. Acad.
Sci. USA 82: 6148-6152);
gene targeting in embryonic stem cells (Thompson et al., Ce1156 (1989), 313-321); electroporation of embryos and sperm-mediated gene transfer (for a review, see for example, U.S.
Pat. No. 4,736,866).
For the purpose of the present invention, transgenic animals include those that carry the recombinant molecule only in part of their cells ("mosaic animals"). The molecule can be integrated either as a single transgene, or in concatamers. Selective introduction of a nucleic acid molecule into a particular cell type is also possible by following, for example, the technique of Lasko et al., Proc. Natl. Acad. Sci.
USA 89 (1992): 6232-6236. Particular cells could also be targeted for molecular incorporation with tissue-specific enhancers. The expression of the integrated molecule can be monitored by standard techniques such as in situ hybridization, Northern Blot analysis, PCR or immunocytochemistry.
Transgenic animals that include a copy of such a nucleic acid molecule introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA
encoding the corresponding protein. In accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.

The present invention has been described in detail by way of illustration and example in order to acquaint others skilled in the art with the invention, its principles and its practical application. Particular formulations and processes of the present invention are not limited to the descriptions of the specific embodiments presented, but rather the descriptions and examples should be viewed in terms of the claims that follow and their equivalents. While some of the examples and descriptions above include some conclusions about the way the invention may function, the inventors do not intend to be bound by those conclusions and functions, but put them forth only as possible explanations.

It is to be further understood that the specific embodiments of the present invention as set forth are not intended as being exhaustive or limiting of the invention, and that many alternatives, modifications and variations will be apparent to those of ordinary skill in the art in light of the foregoing examples and detailed description. Accordingly, this invention is intended to embrace all such alternatives, modifications and variations that fall within the spirit and scope of the following claims.

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Claims (26)

1. A method for identifying an individual who has an altered risk for developing colorectal cancer, comprising detecting a single nucleotide polymorphism (SNP) in any one or more of the following nucleotide bases:
a base located at position 20805662 to position 21149959 on human chromosome 1;
a base located at position 54531998 to position 54563831 on human chromosome 1;
a base located at position 106818235 to position 107115334 on human chromosome 1;
a base located at position 114975727 on human chromosome 1;
a base located at position 49163446 to position 49335916 on human chromosome

2;
a base located at position 25184366 to position 25300483 on human chromosome

3;
a base located at position 156007562 to position 156033905 on human chromosome

4;
a base located at position 82950808 to position 83172329 on human chromosome 6;
a base located at position 129960703 to position 129970245 on human chromosome 6;
a base located at position 11585877 on human chromosome 7;
a base located at position 81554149 to position 81654315 on human chromosome 7;
a base located at position 144628286 to position 144819907 on human chromosome 7;
a base located at position 149242026 on human chromosome 7;
a base located at position 4252805 to position 4257764 on human chromosome 8;
a base located at position 55688038 to position 55886453 on human chromosome 8;
a base located at position 128476625 to position 128495575 on human chromosome 8;
a base located at position 110115339 to position 110130428 on human chromosome 9;
a base located at position 4430296 to position 4543829 on human chromosome 11;
a base located at position 115738853 to position 115747903 on human chromosome 11;
a base located at position 9803997 to position 9820946 on human chromosome 12;
a base located at position 67170429 to position 67276155 on human chromosome 14;
a base located at position 5806139 to position 5830572 on human chromosome 16;
a base located at position 30908917 to position 31050583 on human chromosome 17;
a base located at position 59475942 to position 59492183 on human chromosome 19; and a base located at position 19751933 to position 19778477 on human chromosome 22; or a base in strong linkage disequilibrium with at least one of the foregoing bases.

2. The method of claim 1, which comprises detecting a single nucleotide polymorphism (SNP) in any one or more of the following nucleotide bases:
a base located at position 20805662 to position 21149959 on human chromosome 1;
a base located at position 54531998 to position 54563831 on human chromosome 1;

a base located at position 106818235 to position 107115334 on human chromosome 1;
a base located at position 114975727 on human chromosome 1;
a base located at position 49163446 to position 49335916 on human chromosome 2;
a base located at position 25184366 to position 25300483 on human chromosome 3;
a base located at position 156007562 to position 156033905 on human chromosome 4;
a base located at position 82950808 to position 83172329 on human chromosome 6;
a base located at position 129960703 to position 129970245 on human chromosome 6;
a base located at position 11585877 on human chromosome 7;
a base located at position 81554149 to position 81654315 on human chromosome 7;
a base located at position 144628286 to position 144819907 on human chromosome 7;
a base located at position 149242026 on human chromosome 7;
a base located at position 4252805 to position 4257764 on human chromosome 8;
a base located at position 55688038 to position 55886453 on human chromosome 8;
a base located at position 128476625 to position 128495575 on human chromosome 8;
a base located at position 110115339 to position 110130428 on human chromosome 9;
a base located at position 4430296 to position 4543829 on human chromosome 11;
a base located at position 115738853 to position 115747903 on human chromosome 11;
a base located at position 9803997 to position 9820946 on human chromosome 12;
a base located at position 67170429 to position 67276155 on human chromosome 14;
a base located at position 5806139 to position 5830572 on human chromosome 16;
a base located at position 30908917 to position 31050583 on human chromosome 17;
a base located at position 59475942 to position 59492183 on human chromosome 19; and a base located at position 19751933 to position 19778477 on human chromosome 22; or a base in strong linkage disequilibrium with at least one of the foregoing bases.

3. The method of claim 2, wherein said base is in strong linkage disequilibrium with at least one of the nucleotide bases located as follows:
at position 20805662, 20807307, 20810473, 20812307, 20814435, 20833262, 20834778, 20835387, 20843033, 20843172, 20845152, 20859722, 20860139, 20866984, 20868329, 20869596, 20871652, 20873726, 20885691, 20890966, 20897686, 20897690, 20897946, 20900501, 20901973, 20910482, 20922516, 20925487, 20925556, 20931914, 20934009, 20935818, 20937929, 20939816, 20943571, 20945070, 20945280, 20945717, 20949204, 20949302, 20951449, 20955075, 20958577, 20959014, 20960041, 20965681, 20965980, 20966007, 20969559, 20972644, 20980229, 20984365, 20986738, 20993250, 20994909, 20997023, 20999899, 21000095, 21000981, 21004018, 21006394, 21010403, 21016114, 21022160, 21024702, 21028251, 21033244, 21035367, 21040905, 21041170, 21050902, 21051467, 21055398, 21062830, 21063762, 21068091, 21068874, 21069797, 21070066, 21072609, 21078118, 21082461, 21082628, 21084950, 21106482, 21107684, 21112807, 21120116, 21120469, 21121210, 21127511, 21131101, 21137181, 21140439, 21140663, 21141522, 21141902, 21142192, 21145524, 21149959, 54531998, 54538208, 54548927, 54551090, 54556623, 54557621, 54561302, 54561394, 54562638, 54563585, 54563831, 106818235, 106828844, 106830088, 106891798, 106912949, 106928115, 106930964, 106971827, 106998017, 107004258, 107006719, 107010986, 107011275, 107011305, 107011409, 107011554, 107011627, 107012941, 107014445, 107017707, 107021830, 107024684, 107025142, 107033827, 107034845, 107044596, 107047341, 107048343, 107052637, 107054139, 107056341, 107056364, 107080550, 107081508, 107086826, 107088101, 107091984, 107092704, 107093768, 107096669, 107098220, 107100885, 107103052, 107115313, 107115334, or 114975727 on human chromosome 1;
at position 49163446, 49169518, 49180455, 49183068, 49184463, 49185265, 49186995, 49187513, 49187893, 49189474, 49189694, 49190619, 49191171, 49191484, 49192006, 49195881, 49199434, 49199611, 49203878, 49204013, 49205020, 49205539, 49227109, 49239677, 49239769, 49242500, 49242583, 49244528, 49253703, 49311997, 49319087, 49329514, 49329682, 49332061, 49332761, or 49335916 on human chromosome 2;
at position 25184366, 25188663, 25194200, 25205423, 25207827, 25211158, 25211837, 25235457, 25238040, 25239011, 25239845, 25243914, 25244762, 25244932, 25245547, 25250478, 25264520, 25265009, 25269521, 25273091, 25273425, 25274083, 25275052, 25277488, 25279386, 25280012, 25280571, 25283486, 25283965, 25284812, 25285067, 25287098, 25287161, 25288171, 25291318, 25291410, 25295964, or 25300483 on human chromosome 3;
at position 156007562, 156008015, 156009501, 156010845, 156019936, 156020341, 156027459, 156029231, 156030563, 156032538, or 156033905 on human chromosome 4;
at position 82950808, 83037702, 83052756, 83052893, 83059529, 83059811, 83063355, 83065585, 83065715, 83066965, 83067321, 83079412, 83086171, 83086772, 83087733, 83088471, 83089659, 83092525, 83092537, 83094274, 83094499, 83094576, 83095347, 83095565, 83095939, 83096974, 83097004, 83097222, 83098262, 83098329, 83098352, 83100260, 83101000, 83103870, 83113039, 83114887, 83120523, 83122607, 83127291, 83129590, 83131084, 83137358, 83140060, 83146661, 83147795, 83150543, 83153296, 83155501, 83162032, 83163350, 83165082, 83165771, 83167427, 83167802, 83168404, 83169297, 83169493, 83170215, 83170490, 83170598, 83172329, 129960703, 129968495, or 129970245 on human chromosome 6;
at position 11585877, 81554149, 81559478, 81559837, 81641687, 81648931, 81654315, 144628286, 144628318, 144628632, 144629754, 144629965, 144630098, 144635813, 144643683, 144645286, 144646697, 144669590, 144669600, 144671926, 144672558, 144676393, 144678594, 144678612, 144680315, 144718311, 144720727, 144733992, 144734180, 144734239, 144734742, 144744457, 144745774, 144745875, 144751586, 144752182, 144752705, 144753415, 144753565, 144755233, 144755604, 144755775, 144756961, 144757255, 144759437, 144760563, 144761726, 144766026, 144766794, 144767960, 144768118, 144768579, 144768715, 144770877, 144770905, 144771574, 144771653, 144771867, 144774486, 144774883, 144776678, 144777538, 144778707, 144781332, 144781771, 144782495, 144783026, 144783666, 144784599, 144785299, 144788902, 144791211, 144793063, 144796105, 144799583, 144799675, 144800213, 144800438, 144800519, 144800830, 144801300, 144802085, 144802576, 144803188, 144803650, 144804012, 144804167, 144805193, 144805467, 144806025, 144806327, 144806354, 144808010, 144810732, 144814121, 144814527, 144818301, 144819907, or 149242026 on human chromosome 7;
at position 4252805, 4257185, 4257764, 55688038, 55688723, 55688788, 55689106, 55691506, 55692165, 55698923, 55699691, 55701610, 55704003, 55704066, 55704170, 55714151, 55718398, 55720864, 55724371, 55724624, 55725409, 55729655, 55732233, 55734727, 55734972, 55735628, 55735791, 55736905, 55738068, 55740834, 55741606, 55742554, 55752508, 55760756, 55761309, 55776456, 55783865, 55801936, 55811566, 55821626, 55823685, 55825618, 55845129, 55858095, 55861650, 55870126, 55880446, 55883850, 55886453, 128476625, 128482329, 128482487, 128486686, 128489299, 128490967, 128492309, 128492523, 128492580, or 128495575 on human chromosome 8;
at position 110115339, or 110130428 on human chromosome 9;
at position 4430296, 4430392, 4430569, 4434860, 4440254, 4442501, 4443277, 4443753, 4444427, 4444806, 4446686, 4448408, 4449042, 4449105, 4449910, 4450407, 4450528, 4451604, 4453189, 4453422, 4453492, 4453537, 4453673, 4454017, 4454894, 4532655, 4543829, 115738853, 115739067, 115741985, 115742227, 115742992, 115743244, 115744952, 115745463, or 115747903 on human chromosome 11;
at position 9803997, 9805272, 9807907, 9808088, 9808349, 9809369, 9811239, 9814096, 9814118, 9814380, 9817025, 9817331, 9817664, 9817891, 9818051, 9818837, or 9820946 on human chromosome 12;
at position 67170429, 67187174, 67187885, 67188117, 67194680, 67197723, 67219687, 67233546, 67239521, 67241643, 67257453, 67258104, 67258676, 67266474, or 67276155 on human chromosome 14;
at position 5806139, 5806149, 5806269, 5806460, 5807386, 5807689, 5808267, 5808466, 5808524, 5808701, 5808730, 5809618, 5810450, 5812560, 5813426, 5819886, 5828787, or 5830572 on human chromosome 16;
at position 30908917, 30912424, 30918963, 30926748, 30962717, 30967908, 30967921, 30968168, 30998594, 31001651, 31006594, 31011147, 31013421, 31023017, 31023480, 31024741, 31044721, or 31050583 on human chromosome 17;
at position 59475942, 59483891, 59484573, 59484850, 59485000, 59485642, 59488442, 59488531, 59489660, or 59492183 on human chromosome 19;

at position 19751933, 19752848, 19756298, 19756323, 19756976, 19764380, 19767837, 19769591, 19769618, 19769950, 19771148, 19771633, 19772588, 19772956, 19772978, 19773492, 19773582, 19773965, 19774278, 19774574, 19774735, 19774818, 19775246, 19776791, or 19778477 on human chromosome 22.

4. The method of claim 3, wherein:
when the base at position 20805662 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20807307 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20810473 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20812307 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20814435 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20833262 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20834778 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20835387 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20843033 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20843172 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20845152 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20859722 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20860139 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20866984 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20868329 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 20869596 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20871652 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20873726 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20885691 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20890966 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20897686 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20897690 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20897946 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20901973 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20910482 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20922516 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20925487 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20925556 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20931914 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20934009 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20935818 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20937929 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20939816 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 20943571 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20945070 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20945280 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20945717 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20949204 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20949302 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20951449 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20955075 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20958577 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20959014 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20960041 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20965681 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20965980 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20966007 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20969559 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20972644 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20980229 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20984365 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 20986738 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20993250 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20994909 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20997023 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 20999899 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21000095 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21000981 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21004018 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when'the base at position 21006394 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21010403 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21016114 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21022160 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21024702 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21028251 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21033244 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21035367 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21040905 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21041170 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 21050902 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21051467 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21055398 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21062830 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21063762 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21068091 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21068874 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21069797 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21070066 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21072609 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21078118 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21082461 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21082628 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21084950 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21106482 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21107684 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21112807 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21120116 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 21120469 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21121210 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21127511 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21131101 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21137181 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21140439 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21140663 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21141522 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21141902 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21142192 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21145524 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 21149959 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54531998 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54548927 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54551090 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54556623 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54557621 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54561302 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 54561394 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54562638 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54563585 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 54563831 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106818235 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106828844 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106830088 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106891798 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106912949 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106928115 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106930964 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106971827 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 106998017 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107004258 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107006719 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107010986 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107011275 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107011305 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 107011409 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107011554 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107011627 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107012941 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107014445 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107017707 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107021830 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107024684 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107025142 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107033827 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107034845 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107044596 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107047341 on human chromosome 1 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107048343 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107052637 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107054139 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107056341 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107080550 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 107081508 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107086826 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107088101 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107091984 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107092704 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107093768 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107096669 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107098220 on human chromosome 1 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107100885 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107103052 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107115313 on human chromosome 1 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 107115334 on human chromosome 1 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49163446 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49169518 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49180455 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49183068 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49184463 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49185265 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 49186995 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49187513 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49187893 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49189694 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49190619 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49191171 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49191484 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49192006 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49195881 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49199434 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49199611 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49203878 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49204013 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49205020 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49205539 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49227109 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49239677 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49239769 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 49242500 on human chromosome 2 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49242583 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49244528 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49253703 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49311997 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49319087 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49329514 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49329682 on human chromosome 2 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49332061 on human chromosome 2 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49332761 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 49335916 on human chromosome 2 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25184366 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25188663 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25194200 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25205423 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25207827 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25211158 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25211837 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 25235457 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25238040 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25239011 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25239845 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25243914 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25244932 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25245547 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25250478 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25264520 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25265009 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25269521 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25273091 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25273425 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25274083 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25275052 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25277488 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25279386 on human chromosome 3 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25280012 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 25280571 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25283486 on human chromosome 3 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25283965 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25284812 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25285067 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25287098 on human chromosome 3 is C or is m strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25287161 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25288171 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25291318 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25291410 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25295964 on human chromosome 3 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 25300483 on human chromosome 3 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156007562 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156008015 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156009501 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156019936 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156020341 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156027459 on human chromosome 4 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 156029231 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156030563 on human chromosome 4 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156032538 on human chromosome 4 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 156033905 on human chromosome 4 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 82950808 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83037702 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83052756 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83052893 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83059529 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83059811 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83063355 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83065585 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83065715 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83066965 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83067321 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83079412 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83086171 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83086772 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83087733 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83089659 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83092525 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83092537 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83094274 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83094499 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83094576 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83095347 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83095565 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83095939 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83096974 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83097004 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83097222 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83098262 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83098329 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83098352 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83100260 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83101000 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83103870 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83113039 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83114887 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83120523 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83122607 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83127291 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83129590 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83131084 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83137358 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83140060 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83146661 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83147795 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83150543 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83153296 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83155501 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83162032 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83163350 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83165082 on human chromosome 6 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 83165771 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83167427 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83167802 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83168404 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83169297 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83169493 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83170215 on human chromosome 6 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83170490 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83170598 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 83172329 on human chromosome 6 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 129970245 on human chromosome 6 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 81554149 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 81559478 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 81641687 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 81648931 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 81654315 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144628286 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144628318 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 144628632 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144629754 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144629965 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144630098 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144635813 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144643683 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144645286 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144646697 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144669590 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144669600 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144671926 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144672558 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144676393 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144678594 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144678612 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144680315 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144718311 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144720727 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 144733992 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144734180 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144734239 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144734742 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144744457 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144745774 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144745875 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144751586 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144752182 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144752705 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144753415 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144753565 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144755233 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144755604 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144755775 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144756961 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144757255 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144759437 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 144760563 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144761726 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144766026 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144766794 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144768118 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144768579 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144768715 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144770877 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144770905 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144771574 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144771653 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144771867 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144774486 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144774883 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144776678 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144777538 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144778707 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144781332 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 144781771 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144782495 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144783026 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144783666 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144784599 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144785299 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144788902 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144791211 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144793063 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144796105 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144799583 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144799675 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144800213 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144800438 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144800519 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144800830 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144801300 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144802085 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 144802576 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144803188 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144803650 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144804012 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144804167 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144805193 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144805467 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144806025 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144806327 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144806354 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144808010 on human chromosome 7 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144810732 on human chromosome 7 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144814121 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144814527 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144818301 on human chromosome 7 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 144819907 on human chromosome 7 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4252805 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4257185 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 55688038 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55688723 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55688788 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55689106 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55691506 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55692165 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55698923 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55699691 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55704003 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55704066 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55704170 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55714151 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55718398 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55720864 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55724371 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55724624 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55725409 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55729655 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 55732233 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55734727 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55734972 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55735628 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55735791 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55736905 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55738068 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55740834 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55741606 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55742554 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55752508 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55760756 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55761309 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55776456 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55783865 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55801936 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55811566 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55821626 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 55823685 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55825618 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55845129 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55858095 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55861650 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55870126 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55880446 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55883850 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 55886453 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128482329 on human chromosome 8 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128482487 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128486686 on human chromosome 8 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128489299 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128490967 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128492309 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128492523 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128492580 on human chromosome 8 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 128495575 on human chromosome 8 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 110130428 on human chromosome 9 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4430296 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4430392 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4430569 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4434860 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4440254 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4442501 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4443277 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4443753 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4444427 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4444806 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4446686 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4448408 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4449042 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4449105 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4449910 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4450407 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4450528 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 4451604 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4453189 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4453492 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4453537 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4453673 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4454017 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4454894 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4532655 on human chromosome 11 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 4543829 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115739067 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115741985 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115742227 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115742992 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115 743244 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115744952 on human chromosome 11 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115745463 on human chromosome 11 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 115747903 on human chromosome 11 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9803997 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 9805272 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9807907 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9808088 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9808349 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9809369 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9811239 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9814096 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9814380 on human chromosome 12 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9817025 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9817331 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9817664 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9817891 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9818051 on human chromosome 12 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9818837 on human chromosome 12 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 9820946 on human chromosome 12 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67170429 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67187885 on human chromosome 14 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67188117 on human chromosome 14 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 67194680 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67197723 on human chromosome 14 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67219687 on human chromosome 14 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67233546 on human chromosome 14 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67239521 on human chromosome 14 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67241643 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67257453 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67258104 on human chromosome 14 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67258676 on human chromosome 14 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67266474 on human chromosome 14 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 67276155 on human chromosome 14 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5806139 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5806149 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5806269 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5806460 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5807386 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5807689 on human chromosome 16 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5808267 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 5808466 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5808524 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5808701 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5808730 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5809618 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5810450 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5812560 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5813426 on human chromosome 16 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5819886 on human chromosome 16 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 5828787 on human chromosome 16 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 30912424 on human chromosome 17 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 30918963 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 30926748 on human chromosome 17 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 30962717 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 30967908 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 30967921 on human chromosome 17 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 30968168 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 30998594 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 31001651 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31006594 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31011147 on human chromosome 17 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31013421 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31023017 on human chromosome 17 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31023480 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31024741 on human chromosome 17 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31044721 on human chromosome 17 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 31050583 on human chromosome 17 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59475942 on human chromosome 19 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59483891 on human chromosome 19 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59484573 on human chromosome 19 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59484850 on human chromosome 19 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59485000 on human chromosome 19 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59488442 on human chromosome 19 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59488531 on human chromosome 19 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59489660 on human chromosome 19 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 59492183 on human chromosome 19 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 19751933 on human chromosome 22 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19752848 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19756298 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19756323 on human chromosome 22 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19756976 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19764380 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19767837 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19769591 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19769618 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19769950 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19771148 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19771633 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19772588 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19772956 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19772978 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19773492 on human chromosome 22 is T or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19773965 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19774278 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;

when the base at position 19774574 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19774735 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19774818 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19775246 on human chromosome 22 is G or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19776791 on human chromosome 22 is C or is in strong disequilibrium linkage therewith, then said base exerts a increased risk;
when the base at position 19778477 on human chromosome 22 is A or is in strong disequilibrium linkage therewith, then said base exerts a increased risk.

5. The method of claim 4, wherein the base is selected from one of those specifically enumerated in claim 3.

6. The method of claim 5, wherein the allelic effect is as specified in any of Tables 1 to 25, as it applies to the specified base.

7. An isolated nucleic acid molecule comprising at least 8 (or at least 9, or at least 10, or at least 11, or at least 12, or at least 13, or at least 14, or at least 15, or at least 16, or at least 17, or at least 18, or at least 19, or at least 20, or at least 21, or at least 22, or at least 23, or at least 24, or at least 25, or at least 26, or at least 27, or at least 28, or at least 29, or at least 30, or at least 31, or at least 32, or at least 33, or at least 34, or at least 35, or at least 36, or at least 37, or at least 38, or at least 39, or at least 40, or at least 41, or at least 42, or at least 43, or at least 44, or at least 45, or at least 46, or at least 47, or at least 48, or at least 49, or at least 50, or at least 51, or at least 52, or at least 53, or at least 54, or at least 55, or at least 56, or at least 57, or at least 58, or at least 59, or at least 60, or at least 61, or at least 62, or at least 63, or at least 64, or at least 65, or at least 66, or at least 67, or at least 68, or at least 69, or at least 70, or at least 71, or at least 72, or at least 73, or at least 74, or at least 75, or at least 76, or at least 77, or at least 78, or at least 79, or at least 80, or at least 81, or at least 82, or at least 83, or at least 84, or at least 85, or at least 86, or at least 87, or at least 88, or at least 89, or at least 90, or at least 91, or at least 92, or at least 93, or at least 94, or at least 95, or at least 96, or at least 97, or at least 98, or at least 99, or at least 100 contiguous nucleotides wherein one of the nucleotides is a single nucleotide polymorphism (SNP) selected from those defined in any of claims 1 to 5, or a complement thereof, and optionally, wherein the isolated nucleic acid molecule has a maximum length of 100 said contiguous nucleotides, or a maximum length of 90 said contiguous nucleotides, or a maximum length of 80 said contiguous nucleotides, or a maximum length of 70 said contiguous nucleotides, or a maximum length of 60 said contiguous nucleotides, or a maximum length of 50 said contiguous nucleotides, or a maximum length of 40 said contiguous nucleotides, or a maximum length of 30 said contiguous nucleotides, or a maximum length of 20 said contiguous nucleotides.

8. An amplified polynucleotide containing a single nucleotide polymorphism (SNP) selected from any one of the nucleotide sequences of claims 1 to 5, or a complement thereof, wherein the amplified polynucleotide is between about 16 and about 2000 nucleotides in length, or any length therebetween.

9. An isolated polynucleotide which specifically hybridizes to a nucleic acid molecule of claim 8.

10. The polynucleotide of claim 9 which is 8 to 100 nucleotides in length.

11. The polynucleotide of claim 9 or 10 which is an allele-specific probe.

12. The polynucleotide of any of claims 7 to 10 which is an allele-specific primer.

13. A kit for detecting a single nucleotide polymorphism (SNP) in a nucleic acid molecule, comprising the polynucleotide of any of claims 7 to 12, a buffer, and an enzyme.

14. A method of detecting a single nucleotide polymorphism (SNP) in a nucleic acid molecule, comprising contacting a test sample with a reagent which specifically hybridizes to a SNP in any one of the nucleotide sequences of SEQ ID NOs: 1 to 624 under stringent hybridization conditions, and detecting the formation of a hybridized duplex.

15. The method of claim 14 in which detection is carried out by a process which may be selected from the group consisting of allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism.

16. A method of detecting a variant polypeptide, comprising contacting a reagent with a variant polypeptide encoded by a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOs: 1 to 624 in a test sample, and detecting the binding of the reagent to the polypeptide.

17. A method for identifying an agent useful in therapeutically or prophylactically treating colorectal cancer, comprising contacting the polypeptide corresponding to all or part of the translated product of the gene comprising the polymorphic site, and may be synthetic or naturally occurring, with a candidate agent under conditions suitable to allow formation of a binding complex between the polypeptide and the candidate agent, and detecting the formation of the binding complex or its functional consequence, wherein the presence of the complex identifies said agent.

18. A method for identifying an individual who has an altered risk for developing colorectal cancer, comprising:
(a) providing a sample containing genetic material of the individual;
(b) amplifying the genetic material in the presence of a pair of primers wherein a first of the primers comprises at least 10 consecutive nucleotides selected from one of sequences of SEQ ID NOs: 1 to 605, each located upstream of the base located at position 331 of each sequence and a second primer comprising at least 10 consecutive nucleotides selected from within the same sequence and located downstream of the base located at position 331; and (c) determining the identity of the base in the genetic material that corresponds to position 331.

19. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) accessing a database containing nucleotide sequence data on single nucleotide polymorphisms located between position 20805662 and position 21149959 on human chromosome 1;
(b) determining the position of a said single nucleotide polymorphism on the human chromosome;
(c) storing the position determined in step (b);
(d) providing the identity of a nucleotide base at the position of the single nucleotide polymorphism stored in step (c) for each member of a clinical population that has been diagnosed as having colorectal cancer;
(e) providing the identity of a nucleotide base at the position of the single nucleotide polymorphism stored in step (c) for each member of a control population; and (f) calculating the degree of correlation between the identities of the nucleotide bases provided in steps (d) and (e) and a diagnosis of colorectal cancer in the clinical population.

20. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) determining the nucleotide sequence for each member of a clinical population that has been diagnosed as having colorectal cancer wherein the sequence is located between position 20805662 and position 21149959 on human chromosome 1;

(b) storing the sequence;
(c) accessing a database containing nucleotide sequence data for said sequence;
(d) determining the position of a single nucleotide polymorphism within the sequence;
(e) providing the identity of a nucleotide base at the position of the single nucleotide polymorphism determined in step (d) for each member of a control population; and (f) calculating the degree of correlation between the identities of the nucleotide bases provided in steps (c) and (d) and a diagnosis of colorectal cancer in the clinical population.

21. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) determining the nucleotide sequence for each member of a clinical population that has been diagnosed as having colorectal cancer wherein the sequence is located between position 20805662 and position 21149959 on human chromosome 1;
(b) storing the sequence;
(c) determining the nucleotide sequence, for each member of a control population, corresponding to the sequence stored in step (b);
(d) storing sequence determined in step (c);
(e) determining the position of a single nucleotide polymorphism within the sequence stored in step (b);
and (f) calculating the degree of correlation between the identities of the nucleotide bases at the position determined in step (e) and a diagnosis of colorectal cancer in the clinical population.

22. The method of any of claims 19 to 21, wherein the position of step (a) is:

between position 54531998 and position 54563831 on human chromosome 1;
between position 106818235 and position 107115334 on human chromosome 1;
position 114975727 on human chromosome 1;
between position 49163446 and position 49335916 on human chromosome 2;
between position 25184366 and position 25300483 on human chromosome 3;
between position 156007562 and position 156033905 on human chromosome 4;
between position 82950808 and position 83172329 on human chromosome 6;
between position 129960703 and position 129970245 on human chromosome 6;
position 11585877 on human chromosome 7;
between position 81554149 and position 81654315 on human chromosome 7;
between position 144628286 and position 144819907 on human chromosome 7;
position 149242026 on human chromosome 7;
between position 4252805 and position 4257764 on human chromosome 8;

between position 55688038 and position 55886453 on human chromosome 8;
between position 128476625 and position 128495575 on human chromosome 8;
between position 110115339 and position 110130428 on human chromosome 9;
between position 4430296 and position 4543829 on human chromosome 11;
between position 115738853 and position 115747903 on human chromosome 11;
between position 9803997 and position 9820946 on human chromosome 12;
between position 67170429 and position 67276155 on human chromosome 14;
between position 5806139 and position 5830572 on human chromosome 16;
between position 30908917 and position 31050583 on human chromosome 17;
between position 59475942 and position 59492183 on human chromosome 19; or between position 19751933 and position 19778477 on human chromosome 22.

23. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) accessing a database that includes nucleotide sequence data on single nucleotide polymorphisms located between position 20805662 and position 21149959 on human chromosome 1 different from those listed in Table 1A;
(b) determining the position of a said single nucleotide polymorphism on the human chromosome;
(c) storing the position determined in step (b);
(d) providing the identity of a nucleotide base at the position of the single nucleotide polymorphism stored in step (c) for each member of a population;
(e) determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 1A for each member of the population; and (f) determining whether the nucleotide bases determined in steps (b) and (e), respectively, are in strong linkage disequilibrium with each other, wherein, if the nucleotide bases are in strong disequilibrium with each other, then the single nucleotide polymorphism determined in step (b) can be used for predicting the susceptibility of an individual to colorectal cancer in the same way as the single nucleotide polymorphism of step (e).

24. The method of claim 23, wherein: in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 54531998 and 54563831 on human chromosome 1 different from those listed in Table 2A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 2A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 106818235 and 107115334 on human chromosome 1 different from those listed in Table 3A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 3A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located at position 114975727 on human chromosome 1 different from those listed in Table 4A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 4A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 49163446 and 49335916 on human chromosome 2 different from those listed in Table 5A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 5A for each member of the population;
and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 25184366 and 25300483 on human chromosome 3 different from those listed in Table 6A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 6A for each member of the population;
and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 156007562 and 156033905 on human chromosome 4 different from those listed in Table 7A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 7A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 82950808 and 83172329 on human chromosome 6 different from those listed in Table 8A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 8A for each member of the population;
and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 129960703 and 129970245 on human chromosome 6 different from those listed in Table 9A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 9A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located at position 11585877 on human chromosome 7 different from those listed in Table 10A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 10A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 81554149 and 81654315 on human chromosome 7 different from those listed in Table 11A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 11A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 144628286 and 144819907 on human chromosome 7 different from those listed in Table 12A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 12A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located at position 149242026 on human chromosome 7 different from those listed in Table 13A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 13A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 4252805 and 4257764 on human chromosome 8 different from those listed in Table 14A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 14A for each member of the population;
and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 55688038 and 55886453 on human chromosome 8 different from those listed in Table 15A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 15A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 128476625 and 128495575 on human chromosome 8 different from those listed in Table 16A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 16A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 110115339 and 110130428 on human chromosome 9 different from those listed in Table 17A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 17A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 4430296 and 4543829 on human chromosome 11 different from those listed in Table 18A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 18A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 115738853 and 115747903 on human chromosome 11 different from those listed in Table 19A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 19A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 9803997 and 9820946 on human chromosome 12 different from those listed in Table 20A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 20A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 67170429 and 67276155 on human chromosome 14 different from those listed in Table 21 A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 21A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 5806139 and 5830572 on human chromosome 16 different from those listed in Table 22A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 22A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 30908917 and 31050583 on human chromosome 17 different from those listed in Table 23A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 23A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 59475942 and 59492183 on human chromosome 19 different from those listed in Table 24A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 24A for each member of the population; and/or in step (a), the database includes nucleotide sequence data on the single nucleotide polymorphisms located between position 19751933 and 19778477 on human chromosome 22 different from those listed in Table 25A and step (e) includes determining the identity of a nucleotide base at the position of a single nucleotide polymorphism listed in Table 25A for each member of the population.

25. A method for identifying a correlation between a single nucleotide polymorphism and a susceptibility of an individual to colorectal cancer, comprising:
(a) determining the nucleotide sequence for a member of a clinical population that has been diagnosed as having colorectal cancer, wherein the sequence is located between position 20805662 and position 21149959 on human chromosome 1;
(b) storing the sequence;
(c) determining the identity of the nucleotide base at a position of a single nucleotide polymorphism listed in Table 1 A;
(d) accessing a database containing the nucleotide sequence corresponding to the sequence determined in step (a);
(e) comparing the sequence of step (b) with the sequence of step (d) to determine the position of any single nucleotide polymorphism in the sequence determined in step (a) and located at a position other than that of step (c);
(f) providing the identity of a nucleotide base at the position determined in step (e) for each member of a population;
(g) providing the identity of a nucleotide base at the position of step (c) for each member of the population; and (h) determining whether the nucleotide bases provided in steps (f) and (g), respectively, are in linkage disequilibrium with each other with an r2 value of >0.05, wherein, if the nucleotide bases are in such disequilibrium with each other, then the single nucleotide polymorphism determined in step (e) can be used for predicting the susceptibility of an individual to colorectal cancer in the same way as the single nucleotide polymorphism of step (c).

26. The method of claim 25, wherein: in step (a), the sequence is located between position 54531998 and 54563831 on human chromosome 1, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 2A is determined;
and/or in step (a), the sequence is located between position 106818235 and 107115334 on human chromosome 1, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 3A is determined; and/or in step (a), the sequence is located at position 114975727 on human chromosome 1, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 4A is determined; and/or in step (a), the sequence is located between position 49163446 and 49335916 on human chromosome 2, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 5A is determined; and/or in step (a), the sequence is located between position 25184366 and 25300483 on human chromosome 3, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 6A is determined; and/or in step (a), the sequence is located between position 156007562 and 156033905 on human chromosome 4, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 7A is determined; and/or in step (a), the sequence is located between position 82950808 and 83172329 on human chromosome 6, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 8A is determined; and/or in step (a), the sequence is located between position 129960703 and 129970245 on human chromosome 6, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 9A is determined; and/or in step (a), the sequence is located at position 11585877 on human chromosome 7, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 10A
is determined; and/or in step (a), the sequence is located between position 81554149 and 81654315 on human chromosome 7, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 11A is determined; and/or in step (a), the sequence is located between position 144628286 and 144819907 on human chromosome 7, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 12A is determined; and/or in step (a), the sequence is located at position 149242026 on human chromosome 7, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 13A
is determined; and/or in step (a), the sequence is located between position 4252805 and 4257764 on human chromosome 8, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 14A is determined; and/or in step (a), the sequence is located between position 55688038 and 55886453 on human chromosome 8, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 15A is determined; and/or in step (a), the sequence is located between position 128476625 and 128495575 on human chromosome 8, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 16A is determined; and/or in step (a), the sequence is located between position 110115339 and 110130428 on human chromosome 9, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 17A is determined; and/or in step (a), the sequence is located between position 4430296 and 4543829 on human chromosome 11, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 18A is determined; and/or in step (a), the sequence is located between position 115738853 and 115747903 on human chromosome 11, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 19A is determined; and/or in step (a), the sequence is located between position 9803997 and 9820946 on human chromosome 12, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 20A is determined; and/or in step (a), the sequence is located between position 67170429 and 67276155 on human chromosome 14, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 21A is determined; and/or in step (a), the sequence is located between position 5806139 and 5830572 on human chromosome 16, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 22A is determined; and/or in step (a), the sequence is located between position 30908917 and 31050583 on human chromosome 17, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 23A is determined; and/or in step (a), the sequence is located between position 59475942 and 59492183 on human chromosome 19, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 24A is determined; and/or in step (a), the sequence is located between position 19751933 and 19778477 on human chromosome 22, and in step (c), the identity of the nucleotide base at the position of a single nucleotide polymorphism listed in Table 25A is determined.