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. Wasmuth, H. E., Tag, C. G., Van de Leur, E., Hellerbrand, C., Mueller, T., Berg, T., Puhl, G., Neuhaus, P., Samuel, D., Trautwein, C., Kanse, S. M., & Weiskirchen, R. Hepatology, 49(3):775–80, March, 2009. abstract bibtex 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. 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.
@article{wasmuth_marburg_2009,
title = {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}},
volume = {49},
issn = {1527-3350 (ELECTRONIC); 0270-9139 (LINKING)},
shorttitle = {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}},
abstract = {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. 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.},
number = {3},
journal = {Hepatology},
author = {Wasmuth, H. E. and Tag, C. G. and Van de Leur, E. and Hellerbrand, C. and Mueller, T. and Berg, T. and Puhl, G. and Neuhaus, P. and Samuel, D. and Trautwein, C. and Kanse, S. M. and Weiskirchen, R.},
month = mar,
year = {2009},
keywords = {Adult Aged Alleles Case-Control Studies Cell Proliferation/drug effects Cells, Genetic/ genetics Proto-Oncogene Proteins c-sis Risk Factors Serine Endopeptidases/ genetics},
pages = {775--80},
}
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M.","Weiskirchen, R."],"bibdata":{"bibtype":"article","type":"article","title":"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","volume":"49","issn":"1527-3350 (ELECTRONIC); 0270-9139 (LINKING)","shorttitle":"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","abstract":"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. 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.","number":"3","journal":"Hepatology","author":[{"propositions":[],"lastnames":["Wasmuth"],"firstnames":["H.","E."],"suffixes":[]},{"propositions":[],"lastnames":["Tag"],"firstnames":["C.","G."],"suffixes":[]},{"propositions":["Van","de"],"lastnames":["Leur"],"firstnames":["E."],"suffixes":[]},{"propositions":[],"lastnames":["Hellerbrand"],"firstnames":["C."],"suffixes":[]},{"propositions":[],"lastnames":["Mueller"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Berg"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Puhl"],"firstnames":["G."],"suffixes":[]},{"propositions":[],"lastnames":["Neuhaus"],"firstnames":["P."],"suffixes":[]},{"propositions":[],"lastnames":["Samuel"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Trautwein"],"firstnames":["C."],"suffixes":[]},{"propositions":[],"lastnames":["Kanse"],"firstnames":["S.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Weiskirchen"],"firstnames":["R."],"suffixes":[]}],"month":"March","year":"2009","keywords":"Adult Aged Alleles Case-Control Studies Cell Proliferation/drug effects Cells, Genetic/ genetics Proto-Oncogene Proteins c-sis Risk Factors Serine Endopeptidases/ genetics","pages":"775–80","bibtex":"@article{wasmuth_marburg_2009,\n\ttitle = {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}},\n\tvolume = {49},\n\tissn = {1527-3350 (ELECTRONIC); 0270-9139 (LINKING)},\n\tshorttitle = {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}},\n\tabstract = {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. 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.},\n\tnumber = {3},\n\tjournal = {Hepatology},\n\tauthor = {Wasmuth, H. E. and Tag, C. G. and Van de Leur, E. and Hellerbrand, C. and Mueller, T. and Berg, T. and Puhl, G. and Neuhaus, P. and Samuel, D. and Trautwein, C. and Kanse, S. 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