[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection

Genes & Immunity volume 21, pages 348–359 (2020)Cite this article

Subjects

A Correction to this article was published on 23 November 2020

This article has been updated

Abstract

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10−04) and rs8099917 (P value = 5.5 × 10−04). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10−05). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10−04). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: HCV clearance and rs368234815 marker.
Fig. 2: Schematic representation of the fine mapping analysis performed in this study.
Fig. 3: Genetic structure of the IFNL locus, amplified fragments used for targeted sequencing, and two main variants associated in prior GWAS studies with HCV clearance (rs12979860 and rs368234815).
Fig. 4: Results of the analysis conditioned on rs368234815 and LD patterns of the top associated variants from that analysis.

Similar content being viewed by others

Change history

  • 12 November 2020

    The original version of this Article contained an error in the author name for Thomas R. O’Brien. The family name contained a space and incorrectly appeared as O’ Brien. This has now been corrected in both the PDF and HTML versions of the Article.

  • 23 November 2020

    A Correction to this paper has been published: https://doi.org/10.1038/s41435-020-00119-z

References

  1. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138:1338–45. 1345.e1–7

    Article  CAS  Google Scholar 

  2. Duggal P, Thio CL, Wojcik GL, Goedert JJ, Mangia A, Latanich R, et al. Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann Intern Med. 2013;158:235–45.

    Article  Google Scholar 

  3. Vergara C, Thio CL, Johnson E, Kral AH, O’Brien TR, Goedert JJ, Multi-Ancestry Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus. Gastroenterology. 2019;156:1496–507.

    Article  Google Scholar 

  4. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45:164–71.

    Article  CAS  Google Scholar 

  5. Hong M, Schwerk J, Lim C, Kell A, Jarret A, Pangallo J, et al. Interferon lambda 4 expression is suppressed by the host during viral infection. J Exp Med. 2016;213:2539–52.

    Article  CAS  Google Scholar 

  6. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798–801.

    Article  CAS  Google Scholar 

  7. Tillmann HL, Thompson AJ, Patel K, Wiese M, Tenckhoff H, Nischalke HD, et al. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. Gastroenterology. 2010;139:1586–92. 1592.e1

    Article  CAS  Google Scholar 

  8. Knapp S, Warshow U, Ho KM, Hegazy D, Little AM, Fowell A, et al. A polymorphism in IL28B distinguishes exposed, uninfected individuals from spontaneous resolvers of HCV infection. Gastroenterology. 2011;141:320–5. 325.e1-2

    Article  CAS  Google Scholar 

  9. Aka PV, Kuniholm MH, Pfeiffer RM, Wang AS, Tang W, Chen S, et al. Association of the IFNL4-ΔG allele with impaired spontaneous clearance of hepatitis C virus. J Infect Dis. 2014;209:350–4.

    Article  CAS  Google Scholar 

  10. Chinnaswamy S. Genetic variants at the IFNL3 locus and their association with hepatitis C virus infections reveal novel insights into host-virus interactions. J Interferon Cytokine Res. 2014;34:479–97.

    Article  CAS  Google Scholar 

  11. Spain SL, Barrett JC. Strategies for fine-mapping complex traits. Hum Mol Genet. 2015;24:R111–9.

    Article  CAS  Google Scholar 

  12. Mandelker D, Schmidt RJ, Ankala A, McDonald Gibson K, Bowser M, Sharma H, et al. Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing. Genet Med. 2016;18:1282–9.

    Article  CAS  Google Scholar 

  13. Smith KR, Suppiah V, O’Connor K, Berg T, Weltman M, Abate ML, et al. Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort. Genome Med. 2011;3:57.

    Article  CAS  Google Scholar 

  14. Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. An integrated map of structural variation in 2504 human genomes. Nature. 2015;526:75–81.

    Article  CAS  Google Scholar 

  15. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77.

    Article  CAS  Google Scholar 

  16. Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4:63–8.

    Article  CAS  Google Scholar 

  17. O’Brien TR, Prokunina-Olsson L, Donnelly RP. IFN-lambda4: the paradoxical new member of the interferon lambda family. J Interferon Cytokine Res. 2014;34:829–38.

    Article  Google Scholar 

  18. Wojcik GL, Thio CL, Kao WH, Latanich R, Goedert JJ, Mehta SH, et al. Admixture analysis of spontaneous hepatitis C virus clearance in individuals of African descent. Genes Immun. 2014;15:241–6.

    Article  CAS  Google Scholar 

  19. Li Y, Willer C, Sanna S, Abecasis G. Genotype imputation. Annu Rev Genomics Hum Genet. 2009;10:387–406.

    Article  CAS  Google Scholar 

  20. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1.

    Article  CAS  Google Scholar 

  21. Schaid DJ, Chen W, Larson NB. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet. 2018;19:491–504.

    Article  CAS  Google Scholar 

  22. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296:2225–9.

    Article  CAS  Google Scholar 

  23. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.

    Article  CAS  Google Scholar 

  24. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. 2002;70:425–34.

    Article  Google Scholar 

  25. Kichaev G, Pasaniuc B. Leveraging functional-annotation data in trans-ethnic fine-mapping studies. Am J Hum Genet. 2015;97:260–71.

    Article  CAS  Google Scholar 

  26. Kichaev G, Yang WY, Lindstrom S, Hormozdiari F, Eskin E, Price AL, et al. Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet. 2014;10:e1004722.

    Article  Google Scholar 

  27. Purcell S, Cherny SS, Sham PC. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19:149–50.

    Article  CAS  Google Scholar 

  28. Origa R, Marceddu G, Danjou F, Perseu L, Satta S, Demartis FR, et al. IFNL3 polymorphisms and HCV infection in patients with beta thalassemia. Ann Hepatol. 2015;14:389–95.

    Article  CAS  Google Scholar 

  29. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–4.

    Article  CAS  Google Scholar 

  30. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.

    Article  CAS  Google Scholar 

  31. Fernandez-Rodriguez A, Rallon N, Berenguer J, Jimenez-Sousa MA, Cosin J, Guzman-Fulgencio M, et al. Analysis of IL28B alleles with virologic response patterns and plasma cytokine levels in HIV/HCV-coinfected patients. AIDS. 2013;27:163–73.

    Article  CAS  Google Scholar 

  32. Booth DR, Ahlenstiel G, George J. Pharmacogenomics of hepatitis C infections: personalizing therapy. Genome Med. 2012;4:99.

    Article  CAS  Google Scholar 

  33. Terczynska-Dyla E, Bibert S, Duong FH, Krol I, Jorgensen S, Collinet E, et al. Reduced IFNlambda4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes. Nat Commun. 2014;5:5699.

    Article  CAS  Google Scholar 

  34. O’Brien TR, Pfeiffer RM, Paquin A, Lang Kuhs KA, Chen S, Bonkovsky HL, et al. Comparison of functional variants in IFNL4 and λL3 for association with HCV clearance. J Hepatol. 2015;63:1103–10.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the participants of the study. We also thank Cristian Velarde for the graphic design of the figures.

Funding

R01-013324, 2R01-AI148049, DA-04334, U19-AI088791, HHSN261200800001E, U01-AI35042, U01-AI35043, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35004, U01-AI31834, U01-AI34994, U01-AI34989, U01-AI34993, U01-AI42590, U01-HD32632, R01-HL076902, R01-HD-41224, R01-AI148049-21, R21AI139012, U19-AI082630, U01-AI131314, R01-DA033541, U19-AI066345, DA12568, DA036297, R01-DA09532, R01-DA11860, N02CP91027, H79TI12103, R01-DA16159, R01-DA21550, UL1 RR024996.

Author information

Authors and Affiliations

  1. Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA

    Candelaria Vergara, Priya Duggal, Shruti H. Mehta, Gregory D. Kirk, Sarah J. Wheelan, Genevieve L. Wojcik & Margaret A. Taub

  2. Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    Chloe L. Thio, Ana Valencia, Rachel Latanich, Winston Timp, Andrea L. Cox, Sarah J. Wheelan & David L. Thomas

  3. Universidad Pontificia Bolivariana, Medellin, Colombia

    Ana Valencia

  4. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Thomas R. O’Brien & James J. Goedert

  5. RTI International, Research Triangle Park, NC, USA

    Eric O. Johnson & Alex H. Kral

  6. Liver Unit IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy

    Alessandra Mangia & Valeria Piazzola

  7. Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Francisco, CA, USA

    Marion G. Peters

  8. Rho, Inc., Chapel Hill, NC, USA

    Sharyne M. Donfield

  9. Centers for Disease Control and Prevention, Atlanta, GA, USA

    Brian R. Edlin

  10. University of California San Francisco and Vitalant Research Institute, San Francisco, CA, USA

    Michael P. Busch & Edward L. Murphy

  11. University College London Institute for Liver and Digestive Health, The Royal Free Hospital, London, UK

    Graeme Alexander

  12. Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Arthur Y. Kim

  13. Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Georg M. Lauer & Raymond T. Chung

  14. South West Liver Unit, Plymouth, PL6 8DH, UK

    Matthew E. Cramp

  15. University of Southampton, Southampton General Hospital, Southampton, UK

    Salim I. Khakoo

  16. University of Colorado, Aurora, CO, USA

    Hugo R. Rosen

  17. Department of Internal Medicine and Digestive Diseases, Centre Hospitalier Universitaire Rangueil, UMR 152, Institut de Recherche pour le Développement Toulouse 3 University, Toulouse, France

    Laurent Alric

Authors
  1. Candelaria Vergara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Priya Duggal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chloe L. Thio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ana Valencia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas R. O’Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rachel Latanich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Winston Timp
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eric O. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alex H. Kral
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alessandra Mangia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. James J. Goedert
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Valeria Piazzola
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shruti H. Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Gregory D. Kirk
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Marion G. Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Sharyne M. Donfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Brian R. Edlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Michael P. Busch
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Graeme Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Edward L. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Arthur Y. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Georg M. Lauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Raymond T. Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Matthew E. Cramp
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Andrea L. Cox
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Salim I. Khakoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Hugo R. Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Laurent Alric
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Sarah J. Wheelan
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Genevieve L. Wojcik
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. David L. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Margaret A. Taub
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Candelaria Vergara.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vergara, C., Duggal, P., Thio, C.L. et al. Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection. Genes Immun 21, 348–359 (2020). https://doi.org/10.1038/s41435-020-00115-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-020-00115-3

Search

Advanced search

Quick links