Genetic dissection of host susceptibility to hepatitis C virus through genome-wide association studies – GENHEPC

I. Background and Significance. - A. Genetic predisposition to infectious diseases. In addition to viral, behavioural and environmental factors, it is not farfetched to consider that host genetics may play a considerable role in the natural history of HCV infection. Indeed several key checkpoints in disease course i.e. the infection per se, initial viral clearance, evolution to chronicity, cirrhosis and hepatocellular carcinoma show clear interindividual variability not to mention response to the main antiviral chemotherapy; pegylated interferon-ribavirin. This is reminiscent of our current understanding of the role of host genetics in infectious diseases where resistance/susceptibility to most common, population-wide, infectious diseases are thought to be polygenic and predispose large number of individuals to mainly a single pathogen e.g. HCV, HIV, HBV. Tackling the genetics of such complex disorders i.e. multifactorial has proven to be cumbersome. As a matter of fact, with the exception of the candidate-gene approach which is by nature biased, and given the rarity of multiplex families, the only way forward is to compare large cohorts of patients versus controls through genomewide association studies (GWA). - - B. Hepatitis C Virus Infection. HCV is a major cause of posttransfusion and community-acquired hepatitis in the world. Most HCV-infected individuals develop chronic infection, 10%-20% of whom will develop liver cirrhosis. 1-5% of chronically infected individuals will ultimately die from hepatocellular carcinoma. Chronic HCV infection affects an estimated 200 million individuals world-wide with at least 5 million and 500,000 infected individuals within the European Community and France, respectively. Although substantial progress has been made in the understanding of HCV molecular virology and antiviral innate and adaptive host cell responses, the pathogenesis of HCV infection and mechanisms of viral clearance are still only partially understood. - - II. Specific Aims. Identification of Genetic Factors Associated with HCV Clearance. - - A. Cohorts. - 1. Cohort I: East German Cohort (EG-C). The study of spontaneous clearance of HCV infection is limited by the difficulty to recruit a large number of patients due to the asymptomatic presentation of acute hepatitis C. Thus, a well documented East-German hepatitis C outbreak in 1978/79 involving a large, well-defined cohort of young pregnant women, who received anti-D immunoglobulin contaminated with a single HCV strain (genotype 1b, isolate AD78) represents a unique opportunity to study host factors associated with spontaneous clearance. - 2. Cohort II: Strasbourg Alsace Cohort (SA-C). Treatment-induced HCV clearance can be achieved in about 50% of chronically infected individuals using combination of pegylated IFN-± and ribavirin. Both viral as well as host cell factors appear to be important for treatment-induced virus elimination and termination of liver disease progression. The identification of genetic host cell factors required for viral clearance is still poorly understood. Thus, a well defined large patient cohort with chronic hepatitis C and treatment-induced viral clearance followed at the Strasburg University Hospitals provides an excellent opportunity to identify host factors associated with viral clearance following response to antiviral therapy. - - B. Specific Aims: - Using GWA established in the laboratory of the coordinator we aim to : Specific Aim 1. Identify genes associated with viral clearance in two well defined cohorts with spontaneous and treatment-induced clearance (coordinator and partner 3). Specific Aim 2. Study the functional impact of the identified genes for the HCV life cycle and virus-host interactions in state-of-the-art model systems for HCV infection established in the laboratory of partner 2. Specific Aim 3. Develop a model for the impact of genetic host factors for outcome of HCV infection and pathogenesis. - - III. Brief overview of method...