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

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.

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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.

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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.

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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.

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Correspondence to Jacob George.

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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.

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

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

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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

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