Haplotypic analysis of the MMP-9 gene in relation to coronary artery disease.

Matrix metalloproteinase-9 (MMP-9) plays an important role in the pathogenesis of atherosclerosis, the pathology underlying the majority of coronary artery disease. We previously identified several polymorphisms in the gene encoding MMP-9. In this study we tested the hypothesis that variation in the matrix metalloproteinase-9 gene influences the development of atherosclerosis. Three common polymorphisms, i.e. -1562C>T, R+279Q and +6C>T, were analysed in 1510 white subjects undergoing coronary angiography. Analyses of individual polymorphisms showed that the frequencies of the C/T and T/T genotypes of the -1562C>T polymorphism were significantly higher in patients with coronary stenosis than in those with a normal angiogram. Logistic regression analyses indicated that individuals carrying the -1562T allele had an approx. 1.5-fold higher risk of developing coronary stenosis (OR 1.49, 95% CI 1.039-2.144), which was equivalent to an over 30% reduction in risk of coronary stenosis in individuals not carrying this allele (OR 0.670, 95% CI 0.467-0.963). The three polymorphisms studied were found to be in strong linkage disequilibrium. Haplotype analyses showed that the C-G-C haplotype (-1562C, +279Q and +6C) was associated with a protective effect against atherosclerosis. Individuals carrying this haplotype were at reduced risk of developing coronary stenosis (OR 0.695, 95% CI 0.530.92). Furthermore, the C-G-C haplotype was associated with less severe coronary atherosclerosis, i.e. carriers of this haplotype were at a lower risk of having coronary stenosis in more than one coronary artery (OR 0.796, 95% CI 0.640.99). These data, together with the previous finding that the -1562T allele has a higher transcriptional activity than the -1562C allele, support the notion that genetic variation with an effect on MMP-9 expression influences the development and progression of atherosclerosis.