Abstract 2825: Coronary Disease Associations of Matrix Metalloproteinases 1, 2, 3, & 9 and Tissue Inhibitor Metalloproteinases 1, 2, & 3
Background: The association of matrix metalloproteinases (MMPs) to coronary heart disease is increasingly recognized. The relationship of a single nucleotide polymorphism (SNP) to coronary artery disease (CAD) has been evaluated for multiple MMP genes, but studies of them together are scarce. We studied the association of CAD and SNPs in MMP genes and their tissue inhibitors (TIMPs): MMP-1 (1G/2G), MMP-2 (C-1306T), MMP-3 (5A/6A), MMP-9 (C-1562T & exon 6 G-A [R279Q]), TIMP-1 (T372C), TIMP-2 (A-596C), and TIMP-3 (C249T).
Methods: Patients (N=4526) with angiographically-defined CAD (≥1 lesion of ≥70% stenosis, n=3426) or no CAD (no lesions) were evaluated (those with mild CAD were excluded). Due to linkage disequilibrium, MMP-1 and MMP-3 SNPs (on chromosome 11) were combined as one variable (MMP-1/3) as were the two MMP-9 SNPs. Overall population and subpopulation analyses were performed. Bonferroni correction required p≤0.00833 for significance.
Results: In the overall population, MMP-1/3 was associated with CAD (vs. wild-type 2G2G/6A6A), with increased risk for 2G1G/6A6A (OR=1.41, p=0.018), 2G1G/6A5A (OR=1.44, p=0.001), 2G1G/5A5A (OR=1.50, p=0.006), and 1G1G/5A5A (OR=1.29, p=0.047) (multivariable adjustment: p=0.037, 0.020, 0.035, 0.17, respectively). No effect was found for any other composite genotypes. TIMP-2 had suggestive significance (CC vs. AA: OR=0.082, p=0.045). No associations were found for MMP-2, MMP-9, TIMP-1, or TIMP-3, and no interactions existed between MMPs and their respective TIMPs. Among females, TIMP-1 (on X chromosome) showed a trend (vs. TT, TC: OR=1.24, p=0.08; CC: OR=1.30, p=0.09), as did MMP-2 (vs. CC, TT: OR=1.57, p=0.056), but other sex-specific results were not improved. No smoking interactions were found.
Conclusions: Associations of CAD to composite genotypes across MMP-1 and MMP-3 were found, with weak associations for MMP-2, TIMP-1, and TIMP-2. MMP-1/3 and TIMP-1 were also implicated in this population in previous studies for MI, although the genotypes associated were not always the same. The inconsistency in genotype associations suggests that these SNPs do not adequately account for the genes’ genetic variation and indicate a need for comprehensive evaluation of all genetic variation in these genes.