Whole Exome Sequencing Study of TGFβ Pathway Genes in HCV Liver Fibrosis

Despite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-β pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39-6.69). Our results suggest that endoglin, a key player in TGF-β signaling, is involved in HCV-related liver fibrogenesis.]]>
The data are in the public ftp site.
]]>We recruited adult Caucasian patients (>18 years of age) with chronic HCV infection defined as the presence of circulating HCV RNA tested by reverse transcriptase PCR. The criteria for the inclusion of patients were (a) an available liver biopsy before any treatment; (b) a known presumed date of HCV acquisition (date of the first exposure to blood products, or of beginning of intravenous drug (IVD) use); (c) a low alcohol consumption (less than three or less than two standard drinks a day for men or women, respectively); (d) absence of co-infection with HIV or hepatitis B virus; (e) absence of any coexisting chronic liver disease or hepatocellular carcinoma. The severe fibrosis group included patients (cases) who developed severe fibrosis (METAVIR score F3 or F4) in less than 30 years after the presumed date of HCV infection. The control group included patients who did not develop fibrosis (METAVIR score F0 or F1) more than 20 years after the presumed date of HCV infection in the absence of treatment.]]>