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
✍ Scribed by Hermann E. Wasmuth; Carmen G. Tag; Eddie Van de Leur; Claus Hellerbrand; Tobias Mueller; Thomas Berg; Gero Puhl; Peter Neuhaus; Didier Samuel; Christian Trautwein; Sandip M. Kanse; Ralf Weiskirchen
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 233 KB
- Volume
- 49
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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 VIIactivating 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 PDGF receptor or ␣-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;49:775-780.