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 PDGFbeta receptor or alpha-smooth muscle actin expression but completely abrogates FSAP-mediated inhibition of PDGF-BB-induced proliferation of primary stellate cells in vitro.


CONCLUSIONS
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.
Wasmuth
Hermann E
HE
Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.
Tag
Carmen G
CG
Van de Leur
Eddie
E
Hellerbrand
Claus
C
Mueller
Tobias
T
Berg
Thomas
T
Puhl
Gero
G
Neuhaus
Peter
P
Samuel
Didier
D
Trautwein
Christian
C
Kanse
Sandip M
SM
Weiskirchen
Ralf
R
D000328:Adult; D000368:Aged; D000483:Alleles; D000077214:Becaplermin; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000473:pathology; D006526:Hepatitis C / Q000150:complications* / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics*
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; C433550:HABP2 protein, human; D012697:Serine Endopeptidases