1. Johns Hopkins University, Division of Infectious Diseases, Baltimore, Maryland 21205, USA
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
3. Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina 27708, USA
4. Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA
5. Division of Medicine, Imperial College, London W2 1NY, UK
6. Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, UK
7. Infections & Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20852, USA
8. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
9. Rho, Inc., Chapel Hill, North Carolina 27517, USA
10. University of Colorado Health Sciences Center, Division of Gastroenterology and Hepatology, Aurora, Colorado 80045, USA
11. Blood Systems Research Institute, San Francisco, California 94118, USA
12. Duke Clinical Research Institute and Division of Gastroenterology, School of Medicine, Duke University, Durham, North Carolina 27705, USA
13. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts 02114, USA
14. These authors contributed equally to this work.

Correspondence to: Mary Carrington^2,13 Correspondence and requests for materials should be addressed to M.C. (Email: carringm@mail.nih.gov).

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 clearance^{3, 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-3, 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.