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.

  • Letter
  • Published:

Genetic variation in IL28B and spontaneous clearance of hepatitis C virus

Nature volume 461, pages 798–801 (2009)Cite this article

This article has been updated

Abstract

Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide1. Most (70–80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma2. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance3,4. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment5. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

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

Figure 1: Percentage of HCV clearance by rs12979860 genotype.
Figure 2: Sampling locations, allele frequencies and degree of regional differentiation of the rs12979860 C allele.

Similar content being viewed by others

Change history

  • 08 October 2009

    Two sentences were removed from the text on 8 October 2009.

References

  1. Centers for Disease Control and Prevention Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Recomm. Rep. 47, 1–39 (1998)

    Google Scholar 

  2. Seeff, L. B. Natural history of chronic hepatitis C. Hepatology 36 (suppl. 1). S35–S46 (2002)

    PubMed  Google Scholar 

  3. Cooper, S. et al. Analysis of a successful immune response against hepatitis C virus. Immunity 10, 439–449 (1999)

    Article  CAS  Google Scholar 

  4. Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Rev. Immunol. 5, 215–229 (2005)

    Article  CAS  Google Scholar 

  5. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature advance online publication 10.1038/nature08309 (16 August 2009)

  6. Kenny-Walsh, E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N. Engl. J. Med. 340, 1228–1233 (1999)

    Article  CAS  Google Scholar 

  7. Thomas, D. L. et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. J. Am. Med. Assoc. 284, 450–456 (2000)

    Article  CAS  Google Scholar 

  8. Thio, C. L. Host genetic factors and antiviral immune responses to hepatitis C virus. Clin. Liver Dis. 12, 713–726 (2008)

    Article  Google Scholar 

  9. Thio, C. L., Thomas, D. L. & Carrington, M. Chronic viral hepatitis and the human genome. Hepatology 31, 819–827 (2000)

    Article  CAS  Google Scholar 

  10. McHutchison, J. G. et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N. Engl. J. Med. 361, 580–593 (2009)

    Article  CAS  Google Scholar 

  11. Lindsay, K. L. et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 34, 395–403 (2001)

    Article  CAS  Google Scholar 

  12. Zeuzem, S. et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N. Engl. J. Med. 343, 1666–1672 (2000)

    Article  CAS  Google Scholar 

  13. Villano, S. A., Vlahov, D., Nelson, K. E., Cohn, S. & Thomas, D. L. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 29, 908–914 (1999)

    Article  CAS  Google Scholar 

  14. Goldstein, D. B. Common genetic variation and human traits. N. Engl. J. Med. 360, 1696–1698 (2009)

    Article  CAS  Google Scholar 

  15. Kotenko, S. V. et al. IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunol. 4, 69–77 (2003)

    Article  CAS  Google Scholar 

  16. Sheppard, P. et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nature Immunol. 4, 63–68 (2003)

    Article  CAS  Google Scholar 

  17. Marcello, T. et al. Interferons α and λ inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology 131, 1887–1898 (2006)

    Article  Google Scholar 

  18. Dellgren, C., Gad, H. H., Hamming, O. J., Melchjorsen, J. & Hartmann, R. Human interferon-λ3 is a potent member of the type III interferon family. Genes Immun. 10, 125–131 (2009)

    Article  CAS  Google Scholar 

  19. Lauer, G. M. & Walker, B. D. Hepatitis C virus infection. N. Engl. J. Med. 345, 41–52 (2001)

    Article  CAS  Google Scholar 

  20. Donnelly, R. P., Sheikh, F., Kotenko, S. V. & Dickensheets, H. The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. J. Leukoc. Biol. 76, 314–321 (2004)

    Article  CAS  Google Scholar 

  21. Vlahov, D. et al. The ALIVE study, a longitudinal study of HIV-1 infection in intravenous drug users: description of methods and characteristics of participants. NIDA Res. Monogr. 109, 75–100 (1991)

    CAS  PubMed  Google Scholar 

  22. Goedert, J. J. et al. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N. Engl. J. Med. 321, 1141–1148 (1989)

    Article  CAS  Google Scholar 

  23. Hilgartner, M. W. et al. Hemophilia growth and development study. Design, methods, and entry data. Am. J. Pediatr. Hematol. Oncol. 15, 208–218 (1993)

    Article  CAS  Google Scholar 

  24. Osier, M. V. et al. ALFRED: An allele frequency database for anthropology. Am. J. Phys. Anthropol. 119, 77–83 (2002)

    Article  Google Scholar 

Download references

Acknowledgements

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This research was supported by NIH grants R01DA013324 (D.L.T.), R01DA004334 (G.D.K.), R01HL076902 (M.P.B.), R01DK60590 (H.R.R.) and R01HD41224 (S.M.D.). S.I.K. is a Wellcome Trust Senior Clinical Fellow.

Author Contributions D.L.T., C.L.T., J.G.M., D.B.G. and M.C. designed the study. M.C. directed the study. M.P.M. performed the genotyping. M.P.M. and M.C. wrote the manuscript, with major edits by D.L.T., C.L.T. and D.B.G. The analyses were performed by Y.Q., D.G. and C.O. The samples used in the study were provided by C.L.T., J.K., K.K., S.I.K., G.A., J.J.G., G.D.K., S.M.D., H.R.R., L.H.T., M.P.B. and D.L.T. All authors contributed to preparing the final manuscript.

Author information

Author notes

  1. David L. Thomas, Chloe L. Thio and Maureen P. Martin: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland 21205, USA,

    David L. Thomas & Chloe L. Thio

  2. Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA, and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts 02114, USA ,

    Maureen P. Martin, Ying Qi, Colm O’hUigin & Mary Carrington

  3. Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina 27708, USA ,

    Dongliang Ge & David B. Goldstein

  4. Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA,

    Judith Kidd & Kenneth Kidd

  5. Division of Medicine, Imperial College, London W2 1NY, UK

    Salim I. Khakoo

  6. Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, UK

    Graeme Alexander

  7. Division of Cancer Epidemiology and Genetics, Infections & Immunoepidemiology Branch, National Cancer Institute, Rockville, Maryland 20852, USA,

    James J. Goedert

  8. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA,

    Gregory D. Kirk

  9. Rho, Inc., Chapel Hill, North Carolina 27517, USA ,

    Sharyne M. Donfield

  10. Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, Aurora, Colorado 80045, USA,

    Hugo R. Rosen

  11. Blood Systems Research Institute, San Francisco, California 94118, USA ,

    Leslie H. Tobler & Michael P. Busch

  12. Duke Clinical Research Institute and Division of Gastroenterology, School of Medicine, Duke University, Durham, North Carolina 27705, USA,

    John G. McHutchison

  13. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts 02114, USA ,

    Mary Carrington

Authors
  1. David L. Thomas
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Chloe L. Thio
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Maureen P. Martin
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Ying Qi
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Dongliang Ge
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Colm O’hUigin
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Judith Kidd
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Kenneth Kidd
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Salim I. Khakoo
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Graeme Alexander
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. James J. Goedert
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Gregory D. Kirk
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Sharyne M. Donfield
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Hugo R. Rosen
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Leslie H. Tobler
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Michael P. Busch
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. John G. McHutchison
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. David B. Goldstein
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Mary Carrington
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Mary Carrington.

Supplementary information

Supplementary Information

This file contains Supplementary Notes, Supplementary Tables S1-S3, Supplementary Figure S1 with Legend and a Supplementary Reference. (PDF 295 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thomas, D., Thio, C., Martin, M. et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461, 798–801 (2009). https://doi.org/10.1038/nature08463

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08463

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing