A Functional Polymorphism of the Stromelysin Gene (MMP3) May Influence Disease Progression in HCV Infection

The outcome following infection with HCV is highly variable and the determinants of disease progression are poorly defined. Stromelysin is a member of the Matrix Metalloproteinase (MMP) family of enzymes which regulate extracellular matrix degradation and fibrosis. Recent studies suggest that a functional polymorphism in the stromelysin gene (MMP3) is associated with both increased susceptibility (risk) and progression of the fibrotic liver disease, primary sclerosing cholangitis. The aim of the present study was to determine whether this polymorphism is indicative of prognosis and outcome following HCV infection. The MMP3–1171 5A/6A polymorphism was determined in a homogenous cohort of 212 Irish women infected with HCV genotype 1b after the administration of contaminated anti-D immunoglobulin in 1977/8. A standard ARMS-PCR technique was used throughout. The overall genotype distribution was similar to that of racially matched controls. There was no significant difference in genotype distribution between those with persistent viraemia (n=131, 5A/5A (24.4%), 5A/6A (50.4%), 6A/6A (25.2%) and those with spontaneous (untreated) viral clearance (n=81, 26%, 57.1%, 16.9%). Of the 131 HCV RNA + patients, 82 (62%) had established fibrosis on liver biopsy. Among patients with the 5A/5A homozygous genotype, 74.2% had fibrosis on biopsy compared with 61% of non 5A/5A genotypes, which just failed to reach statistical significance (p=0.06). These data suggest that the 5A/5A genotype may predispose to the development of hepatic fibrosis in HCV infection. Identification of a genetic marker predictive of fibrosis would enable therapy to be tailored towards those most likely to develop progressive disease.