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Genetic variation in IL28B and spontaneous clearance of hepatitis C virus

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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.

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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.

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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.

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Correspondence to Mary Carrington.

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

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