A novel nonsynonymous variant of matrix metalloproteinase-7 confers risk of liver cirrhosis
Journal
Hepatology
Journal Volume
50
Journal Issue
4
Pages
1184-1193
Date Issued
2009
Author(s)
Abstract
Liver cirrhosis is characterized by progressive accumulation of extracellular matrix following chronic liver injuries. In the extracellular space, the constant turnover of liver matrix is regulated by the matrix metalloproteinase (MMP) class of enzyme. To assess whether genetic variations in MMP would result in diversity of liver cirrhosis, a case-control study of 320 patients with hepatocellular carcinoma, with or without cirrhosis, was conducted. Ten single-nucleotide polymorphism markers from four potential fibrosis-associated genes were selected for genotyping. Among these genes, a nonsynonymous single-nucleotide polymorphism which generates the variation of Gly-137 and Asp-137 in the MMP-7 gene was found to be strongly associated with the development of liver cirrhosis. In contrast to MMP-7(Gly-137) that predominantly secretes out into the cell culture medium, the cirrhosis-associated MMP-7(Asp-137) variant is preferentially localized on the extracellular membranes where it exerts its proteolytic activity on pericellular substrates. Functional analysis demonstrated an increased ability of the MMP-7(Asp-137) variant to associate with the cell surface CD151 molecule. In wound-healing and Boyden chamber assays, cell motility was specifically enhanced with the expression of MMP-7(Asp-137) as compared to the cells expressing MMP-7(Gly-137). These results demonstrate that the MMP-7(Asp-137) variant confers a gain-of-function phenotype for MMP-7. Conclusion: We have identified a novel genetic association of MMP-7(Asp-137) variant with liver cirrhosis in patients with hepatocellular carcinoma. Whether the MMP-7 variant can be a new marker for liver cirrhosis will be further studied. Copyright ? 2009 by the American Association for the Study of Liver Diseases.
SDGs
Other Subjects
aspartic acid; glycine; matrilysin; biological marker; CD151 antigen; leukocyte antigen; matrilysin; adult; article; case control study; cell motility; controlled study; enzyme localization; enzyme release; extracellular space; female; genetic association; genetic risk; genetic variability; genotype; human; human cell; human tissue; liver cell carcinoma; liver cirrhosis; major clinical study; male; pathogenesis; phenotype; priority journal; protein degradation; protein expression; protein protein interaction; single nucleotide polymorphism; aged; cell membrane; genetic predisposition; genetics; Ito cell; liver cell carcinoma; liver cirrhosis; liver tumor; metabolism; middle aged; pathology; risk factor; Adult; Aged; Antigens, CD; Biological Markers; Carcinoma, Hepatocellular; Case-Control Studies; Cell Membrane; Female; Genetic Predisposition to Disease; Genotype; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Matrix Metalloproteinase 7; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors
Type
journal article