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Genetic variation inIL28B predicts hepatitis C treatment-induced viral clearance

Naturevolume 461, pages399–401 (2009)Cite this article

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Abstract

Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America1. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-α-2b (PegIFN-α-2b) or -α-2a (PegIFN-α-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near theIL28B gene, encoding interferon-λ-3 (IFN-λ-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 × 10-25) and African-Americans (P = 2.06 × 10-3). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

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Figure 1:Percentage of SVR by genotypes of rs12979860.
Figure 2:Genomic overview of the region of 19q13.13 surrounding the genome-wide significant determinant of response to treatment and including theIL28B gene.
Figure 3:Rate of SVR and rs12979860 C-allele frequency in diverse ethnic groups.

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Change history

  • 17 September 2009

    The x-axis label in Figure 3 was corrected on 17 September 2009.

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Acknowledgements

We are indebted to the IDEAL principal investigators, the study coordinators, nurses and patients involved in the study. We also recognize E. Gustafson, P. Savino, D. Devlin, S. Noviello, M. Geffner, J. Albrecht and A. C. Need for their contributions to the study. This study was funded by Schering-Plough Research Institute, Kenilworth, New Jersey. A.J.T. received funding support from the National Health and Medical Research Council of Australia and the Gastroenterological Society of Australia.

Author Contributions D.G., J.F., A.J.T. and J.S.S. contributed equally to this work. D.G., J.F. and A.J.T. performed the statistical and bioinformatical analyses. J.F. and A.J.T. defined the clinical phenotypes. K.V.S. performed the genotyping. D.B.G. and D.G. drafted the manuscript. J.S.S., J.G.M. and D.B.G. designed the study. All authors collected and analysed data and contributed to preparing the manuscript.

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Authors and Affiliations

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

    Dongliang Ge, Jacques Fellay, Kevin V. Shianna, Thomas J. Urban, Erin L. Heinzen & David B. Goldstein

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

    Alexander J. Thompson, Andrew J. Muir & John G. McHutchison

  3. Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA ,

    Jason S. Simon, Ping Qiu & Arthur H. Bertelsen

  4. Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA ,

    Mark Sulkowski

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  1. Dongliang Ge

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Corresponding author

Correspondence toDavid B. Goldstein.

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Competing interests

Competing Interests: J.G.M. and D.B.G. received research and grant support from Schering-Plough. J.G.M., A.J.M., M.S. and D.B.G. received consulting fees or acted in an advisory capacity for Schering-Plough. J.S.S., P.Q. and A.H.B. are employees of Schering-Plough. D.G., J.F., J.S.S., K.V.S., T.J.U., A.H.B. and D.B.G. are inventors of a patent application based on this finding.

Supplementary information

Supplementary Information

This file contains Supplementary Notes, Supplementary Tables S1-S8, Supplementary Box S1, Supplementary Figure S1 with Legend and Supplementary References. (PDF 440 kb)

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Ge, D., Fellay, J., Thompson, A.et al. Genetic variation inIL28B predicts hepatitis C treatment-induced viral clearance.Nature461, 399–401 (2009). https://doi.org/10.1038/nature08309

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Editorial Summary

Individual responses to hepatitis C virus

Hepatitis C is one of the most common infections in the world. Many of its estimated 170 million sufferers live with the disease for years with no serious symptoms, but in about one in four patients it leads to cirrhosis of the liver. The discovery of a biomarker that predicts an individual's response to hepatitis C treatment raises the possibility that clinical outcomes could be improved by raising patient compliance to the often demanding interferon treatment regime. The new marker is a 'single letter' genetic variant — a C (cytosine) replacing a T (thymidine) in a segment of DNA near theIL28B gene that encodes interleukin 28B (interferon-γ-3). This finding goes some way towards explaining the different treatment outcomes between individuals of European (highIL28B frequency), African and Asian ancestry. And importantly, it is of immediate clinical utility.

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