A novel nonsynonymous variant of matrix metalloproteinase‐7 confers risk of liver cirrhosis

• Published in: Hepatology (Baltimore, Md.) Vol. 50; no. 4; pp. 1184 - 1193
• Main Authors: Hung, Tzu‐Min, Chang, Shin C., Yu, Wei‐Hsuan, Wang, Yu‐Wen, Huang, Cheng, Lu, Shao‐Chun, Lee, Po‐Huang, Chang, Ming‐Fu
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2009; Wiley
• Subjects: Adult; Aged; Antigens, CD - metabolism; Biological and medical sciences; Biomarkers - metabolism; Carcinoma, Hepatocellular - metabolism; Case-Control Studies; Cell Membrane - metabolism; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genetic Predisposition to Disease - genetics; Genotype; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Humans; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Neoplasms - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Matrix Metalloproteinase 7 - genetics; Matrix Metalloproteinase 7 - metabolism; Medical sciences; Middle Aged; Other diseases. Semiology; Polymorphism, Single Nucleotide - genetics; Risk Factors; Tetraspanin 24; Cirrhosis; Digestive diseases; Hepatic disease; Liver; Risk factor; Gastroenterology
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.23137

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. (HEPATOLOGY 2009.)