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.

IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy

Nature Genetics volume 41, pages 1100–1104 (2009)Cite this article

Abstract

Hepatitis C virus (HCV) infects 3% of the world's population. Treatment of chronic HCV consists of a combination of PEGylated interferon-α (PEG-IFN-α) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-α/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFNλ3; rs8099917 combined P = 9.25 × 10−9, OR = 1.98, 95% CI = 1.57–2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-α.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: IL28A, IL28B and IL29 fine mapping.
Figure 2: Plot of qRT-PCR showing the relative expression levels of IL28A and IL28B against the rs8099917 genotype in healthy individuals.

References

  1. World Health Organization (WHO). Hepatitis C. Fact Sheet No. 164. Revised October 2000 http://www.who.int/mediacentre/factsheets/fs164/en/ (2000).

  2. Micallef, J.M., Kaldor, J.M. & Dore, G.J. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J. Viral Hepat. 13, 34–41 (2006).

    Article  CAS  Google Scholar 

  3. Hoofnagle, J.H. Course and outcome of hepatitis C. Hepatology. 36, S21–S29 (2002).

    PubMed  Google Scholar 

  4. Thomas, D.L. & Seeff, L.B. Natural history of hepatitis C. Clin. Liver Dis. 9, 383–398, vi (2005).

    Article  Google Scholar 

  5. Di Bisceglie, A.M. & Hoofnagle, J.H. Optimal therapy of hepatitis C. Hepatology. 36, S121–S127 (2002).

    PubMed  Google Scholar 

  6. David, M. Signal transduction by type I interferons. Biotechniques (Oct), S58–S65 (2002).

    Article  Google Scholar 

  7. Der, S.D., Zhou, A., Williams, B.R. & Silverman, R.H. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc. Natl. Acad. Sci. USA 95, 15623–15628 (1998).

    Article  CAS  Google Scholar 

  8. de Veer, M.J. et al. Functional classification of interferon-stimulated genes identified using microarrays. J. Leukoc. Biol. 69, 912–920 (2001).

    CAS  PubMed  Google Scholar 

  9. Taylor, M.W. et al. Global effect of PEG-IFN-alpha and ribavirin on gene expression in PBMC in vitro. J. Interferon Cytokine Res. 24, 107–118 (2004).

    Article  CAS  Google Scholar 

  10. Tan, H. et al. Global transcriptional profiling combination of type I and type II demonstrates the interferon enhances antiviral and immune responses at clinically relevant doses. J. Interferon Cytokine Res. 25, 632–649 (2005).

    Article  CAS  Google Scholar 

  11. Taylor, M.W. et al. Changes in gene expression during pegylated interferon and ribavirin therapy of chronic hepatitis C virus distinguish responders from non-responders to antiviral therapy. J. Virol. 81, 3391–3401 (2007).

    Article  CAS  Google Scholar 

  12. Fried, M.W. et al. A multicenter, randomized trial of daily high-dose interferon-alfa 2b for the treatment of chronic hepatitis c: pretreatment stratification by viral burden and genotype. Am. J. Gastroenterol. 95, 3225–3229 (2000).

    Article  CAS  Google Scholar 

  13. Manns, M.P. et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 358, 958–965 (2001).

    CAS  Google Scholar 

  14. Fried, M.W. et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 347, 975–982 (2002).

    CAS  Google Scholar 

  15. Hadziyannis, S.J. et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann. Intern. Med. 140, 346–355 (2004).

    Article  CAS  Google Scholar 

  16. Zeuzem, S. et al. Expert opinion on the treatment of patients with chronic hepatitis C. J. Viral Hepat. 16, 75–90 (2009).

    Article  CAS  Google Scholar 

  17. Kraft, P. et al. Beyond odds ratios--communicating disease risk based on genetic profiles. Nat. Rev. Genet. 10, 264–269 (2009).

    Article  CAS  Google Scholar 

  18. Weiss, S.T. et al. Creating and evaluating genetic tests predictive of drug response. Nat. Rev. Drug Discov. 7, 568–574 (2008).

    Article  CAS  Google Scholar 

  19. Selzner, N. & McGilvray, I. Can genetic variations predict HCV treatment outcomes? J. Hepatol. 49, 494–497 (2008).

    Article  Google Scholar 

  20. Aurora, R., Donlin, M.J., Cannon, N.A. & Tavis, J.E. Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans. J. Clin. Invest. 119, 225–236 (2009).

    CAS  PubMed  Google Scholar 

  21. Samarajiwa, S.A., Forster, S., Auchettl, K. & Hertzog, P.J. INTERFEROME: the database of interferon regulated genes. Nucleic Acids Res. 37, D852–D857 (2009).

    Article  CAS  Google Scholar 

  22. de Bakker, P.I.W. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).

    Article  CAS  Google Scholar 

  23. Li, M., Liu, X., Zhou, Y. & Su, S.B. Interferon-lambdas: the modulators of antivirus, antitumor, and immune responses. J. Leukoc. Biol. 86, 23–32 (2009).

    Article  CAS  Google Scholar 

  24. Mihm, S. et al. Interferon type I gene expression in chronic hepatitis C. Lab. Invest. 84, 1148–1159 (2004).

    Article  CAS  Google Scholar 

  25. Fox, B.A., Sheppard, P.O. & O'Hara, P.J. The role of genomic data in the discovery, annotation and evolutionary interpretation of the interferon-lambda family. PLoS One 4, e4933 (2009).

    Article  Google Scholar 

  26. Coccia, E.M. et al. Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur. J. Immunol. 34, 796–805 (2004).

    Article  CAS  Google Scholar 

  27. Ank, N. et al. Lambda interferon (IFNλ), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J. Virol. 80, 4501–4509 (2006).

    Article  CAS  Google Scholar 

  28. Doyle, S.E. et al. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology. 44, 896–906 (2006).

    Article  CAS  Google Scholar 

  29. Sommereyns, C. et al. IFN-lambda is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 4, e1000017 (2008).

    Article  Google Scholar 

  30. Ank, N. et al. An Important Role for Type III Interferon (IFNλ/IL-28) in TLR-Induced Antiviral Activity. J. Immunol. 180, 2474–2485 (2008).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  32. Sirén, J. et al. IFN-a regulates TLR-dependent gene expression of IFN-a, IFN-b, IL-28 and IL-29. J. Immunol. 174, 1932–1937 (2005).

    Article  Google Scholar 

  33. Robek, M.D. et al. Lambda interferon inhibits hepatitis B and C virus replication. J. Virol. 79, 3851–3854 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  35. Österlund, P.I. et al. IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes. J. Immunol. 179, 3434–3442 (2007).

    Article  Google Scholar 

  36. Dellgren, C. et al. Human interferon-lambda3 is a potent member of the type III interferon family. Genes Immun. 10, 125–131 (2009).

    Article  CAS  Google Scholar 

  37. Zhu, H. & Liu, C. Interleukin-1 inhibits hepatitis C virus subgenomic RNA replication by activation of extracellular regulated kinase pathway. J. Virol. 77, 5493–5498 (2003).

    Article  CAS  Google Scholar 

  38. Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    Article  CAS  Google Scholar 

  39. Saito, A. & Kamatani, N. Strategies for genome-wide association studies: optimization of study designs by the stepwise focusing method. J. Hum. Genet. 47, 360–365 (2002).

    Article  CAS  Google Scholar 

  40. Skol, A.D. et al. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

    Article  CAS  Google Scholar 

  41. Price, A.L. et al. Principal component analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  42. Patterson, N.J., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    Article  Google Scholar 

  43. Bersaglieri, T. et al. Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 74, 1111–1120 (2004).

    Article  CAS  Google Scholar 

  44. Coelho, M. et al. Microsatellite variation and evolution of human lactase persistence. Hum. Genet. 117, 329–339 (2005).

    Article  CAS  Google Scholar 

  45. WTCCC. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  46. Tian, C. et al. Analysis and application of European genetic substructure using 300K SNP information. PLoS Genet. 4, e4 (2008).

    Article  Google Scholar 

  47. Sasieni, P.D. From genotype to genes: doubling the sample size. Biometrics 53, 1253–1261 (1997).

    Article  CAS  Google Scholar 

  48. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  Google Scholar 

  49. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  50. Parcell, S. et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Gen. 81, 559–575 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

V.S., D.R.B., G.J.S. and J.G. were supported by National Health and Medical Research Council Project grant 402577 and the Robert W. Storr Bequest to the University of Sydney. M.Bahlo has a National Health and Medical Research Council Career Development Award fellowship. T.B. is supported by the German Competence Network for Viral Hepatitis (Hep-Net), funded by the German Ministry of Education and Research (BMBF, grant number 01 KI 0437), the EU-Vigilanz network of excellence combating viral resistance (VIRGIL, project number LSHM-CT-2004-503359), and the BMBF project Host and viral determinants for susceptibility and resistance to hepatitis C virus infection (FKZ: 01KI0411; project B). D.S. and M.Bassendine are funded by a Medical Research Council UK project grant G0502028. We would like to thank all subjects for their valuable participation in this study.

Author information

Authors and Affiliations

  1. Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, Australia

    Vijayaprakash Suppiah & Jacob George

  2. Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia

    Vijayaprakash Suppiah, Graeme J Stewart & David R Booth

  3. The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Victoria, Australia

    Max Moldovan & Melanie Bahlo

  4. Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse, Bonn, Germany

    Golo Ahlenstiel & Ulrich Spengler

  5. Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany

    Thomas Berg & Tobias Müller

  6. Department of Gastroenterology and Hepatology, Nepean Hospital, Penrith, Sydney, Australia

    Martin Weltman & Vincenzo Fragomeli

  7. Department of Internal Medicine, University of Turin, Liver Physiopathology Lab, Torino, Italy

    Maria Lorena Abate & Antonina Smedile

  8. Liver Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK

    Margaret Bassendine & David Sheridan

  9. National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia

    Gregory J Dore

  10. St. Vincent's Hospital, Sydney, Australia

    Gregory J Dore

  11. Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

    Elizabeth Powell

  12. The University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

    Elizabeth Powell

  13. Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, Australia

    Stephen Riordan

Authors
  1. Vijayaprakash Suppiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Max Moldovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Golo Ahlenstiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martin Weltman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Lorena Abate
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Margaret Bassendine
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ulrich Spengler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gregory J Dore
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Elizabeth Powell
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stephen Riordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David Sheridan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Antonina Smedile
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Vincenzo Fragomeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tobias Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Melanie Bahlo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Graeme J Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. David R Booth
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Jacob George
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Hepatitis C Study

Contributions

V.S., G.J.S., D.R.B. and J.G. designed the study and wrote the manuscript. V.S. did the genotyping. M.M., M.Bahlo, and V.S. did the statistical analysis. Samples were phenotyped and collected by J.G., T.M., V.F., A.S., D.S., S.R., E.P., G.J.D., U.S., M.Bassendine., M.L.A., M.W., T.B. and G.A. All authors read and contributed to the manuscript.

Corresponding author

Correspondence to Jacob George.

Ethics declarations

Competing interests

The authors have filed a provisional patent application on the intention of designing a genetic test kit based on the variants described in this paper.

Additional information

A full list of members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–4, Supplementary Figures 1 and 2 and Supplementary Note (PDF 2378 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Suppiah, V., Moldovan, M., Ahlenstiel, G. et al. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nat Genet 41, 1100–1104 (2009). https://doi.org/10.1038/ng.447

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.447

This article is cited by

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