Single nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes may be associated with myocardial infarction (MI) and coronary artery disease (CAD), but studies of multiple MMP genes and their tissue inhibitors (TIMPs) are scarce. Further, differentiation of predictive ability by endpoint (MI vs. CAD) has not been addressed. This study evaluated the association with MI of SNPs in genes encoding MMPs 1, 2, 3, and 9 and TIMPs 1, 2, and 3.
Genotypes of patients (N=5,148) with MI (n=1,693) and angiographically-defined CAD (=1 lesion of =70% stenosis, n=1,967) were compared to MI-free (n=3,455) and non-CAD patients (n=1,122), respectively. Due to linkage disequilibrium, MMP-1 and MMP-3 SNPs (chromosome 11) were combined, as were the two MMP-9 SNPs.
For MI, only MMP-9 group CT/RQ (OR=1.25, p=0.007 vs. wild-type CC/RR) had greater MI risk, with TT/QQ having a weak trend (OR=1.43, p=0.10). These findings remained (CT/RQ) or were strengthened (TT/QQ) after full adjustment. For CAD, association was found for MMP-1/-3 groups 2G1G/6A6A (OR=1.45, p=0.022), 2G1G/6A5A (OR=1.49, p=0.001), 2G1G/5A5A (OR=1.64, p=0.003), and 1G1G/5A5A (OR=1.35, p=0.035) compared to wild-type.
Composite MMP-9 genotypes but not other SNPs were associated with MI, while MMP-1/-3 genotypes were CAD-associated. The largest MMP/TIMP gene study to date, this study suggests care in selection and definition of clinical phenotypes. Further, this suggests that the evaluated SNPs only approximately account for intra-genic variation in these genes and that comprehensive evaluation of all variation in these genes should better elucidate associations with MI and CAD phenotypes.