The Marburg I variant (G534E) of the factor VII–activating protease determines liver fibrosis in hepatitis C infection by reduced proteolysis of platelet‐derived growth factor BB

Genetic risk factors play an important role for the progression of liver fibrosis in chronic hepatitis C virus (HCV) infection, but functional data on specific alleles and their related proteins are limited. Platelet‐derived growth factor BB (PDGF‐BB) is one of the strongest mitogens for hepatic stellate cells and is considered as a critical soluble mediator of liver fibrosis in vitro and in vivo. The biological activity of PDGF‐BB is dependent on its degradation by the factor VII–activating protease (FSAP). Here, we demonstrate that a coding polymorphism (G534E) in the gene for FSAP is significantly associated with severe HCV‐induced liver fibrosis (odds ratio, 2.59; P = 0.017), which is independent of age, gender, and presence of diabetes in multivariate analysis. These genetic findings were replicated in a cohort of patients with liver transplantation due to HCV‐induced cirrhosis (OR, 2.56; P = 0.011). Functional dissection of the association demonstrates that the single amino acid change encoded by G534E in the FSAP protein does not influence PDGFβ receptor or α‐smooth muscle actin expression but completely abrogates FSAP‐mediated inhibition of PDGF‐BB–induced proliferation of primary stellate cells in vitro. Conclusion: The G534E variant of FSAP is a risk locus for HCV‐induced liver fibrosis and cirrhosis by determining PDGF‐BB–mediated hepatic stellate cell proliferation through a single amino acid substitution in FSAP. FSAP G534E might be useful for risk stratification in patients with HCV infection. (HEPATOLOGY 2009.)