Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance

Abstract

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 the IL28B gene that encodes interleukin 28B (interferon-γ-3). This finding goes some way towards explaining the different treatment outcomes between individuals of European (high IL28B frequency), African and Asian ancestry. And importantly, it is of immediate clinical utility. 170 million people worldwide are chronically infected with hepatitis C virus (HCV), which is the leading cause of cirrhosis in North America. Many patients are not cured by the current recommended treatment regime, with patients of European ancestry having a higher probability of being cured than those of African ancestry. Here, a genetic polymorphism near the IL28B gene is found to be associated with a better response to treatment; it occurs with higher frequency in European populations. 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 the IL28B 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.