Genetic variation in IL28B and spontaneous clearance of hepatitis C virus

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 worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. 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. 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 treatment. 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.

Figure 1

Percentage of HCV clearance by rs12979860 genotype. Data are shown for all patients, as well as whites and blacks separately.

Figure 2

Sampling locations, allele frequencies and degree of regional differentiation of the rs12979860 C allele. (A) The numbers identifying populations are given in Table 3. The pie charts show the frequency of the C (green) and T (blue) alleles in each population sampled. (B) Frequency distribution of F_ST values for 1062 SNPs from 32 of the samples grouped into six regions (Africa, Europe, South Asia, Southeast Asia, East Asia, Oceania). The red arrow indicates the position of the estimated F_ST for rs12979860.