Haplotype Effect of the Matrix Metalloproteinase-1 Gene on Risk of Myocardial Infarction

Abstract

Myocardial infarction (MI) is commonly caused by atherosclerotic plaque rupture following excessive degradation of collagen fibers in the atherosclerotic lesion. We investigated whether interindividual variability in risk of MI was related to polymorphisms in the gene encoding matrix metalloproteinase (MMP)-1, a key fibrillar collagen-degrading enzyme. Several single nucleotide polymorphisms in the MMP1 gene promoter were identified following sequencing DNA samples from 30 individuals. An analysis of the polymorphisms in a cohort of British whites with coronary atherosclerosis, including 639 patients with MI and 538 non-MI subjects, revealed a haplotype effect of the -519A>G and -340T>C polymorphisms on risk of MI, with the A(-519)-C(-340) and G(-519)-T(-340) haplotypes being protective (odds ratio=0.70 [0.57 to 0.86]; P=0.0007), whereas the G(-519)-C(-340) haplotype increased MI risk (odds ratio=1.94 [1.15 to 3.28]; P=0.013). This finding was replicated in a subsequent analysis of 387 Swedish MI patients and 387 healthy controls (odds ratio=0.70 [0.55 to 0.89], P=0.003, for A(-519)-C(-340) and G(-519)-T(-340); odds ratio=1.54 [0.97 to 2.46], P=0.07, for G(-519)-C(-340)). In vitro assays showed that compared with the A(-519)-T(-340) haplotype, the A(-519)-C(-340) and G(-519)-T(-340) haplotypes had lower promoter activity, whereas the G(-519)-C(-340) haplotype had greater promoter strength, in driving gene expression in human macrophages. Haplotype-specific differences in MMP1 mRNA level in atherosclerotic tissues were also detected. The data indicate that MMP1 gene variation is a genetic factor contributing to interindividual differences in MI risk.

Influence of LPS, TNF, TGF-�1 and IL-4 on the expression of MMPs, TIMPs and selected cytokines in rat synovial membranes incubated in vitro

“…MMP1a is able to degrade type I, II and III fibrillar collagen (99,100). It is produced by fibroblasts as procollagenase (101) and is activated by MMP3 (stromelysin) (102).…”

Association of Genetic Variants with Chronic Kidney Disease in Japanese Individuals

“…The Ϫ519A3 G polymorphism of MMP1, which is located in the promoter region of the gene, has been related to the risk of myocardial infarction as part of a haplotype including other polymorphisms of MMP1 (15). In addition, the G allele of this polymorphism was associated with an increased intima-media thickness of the carotid artery in a German population with hypertension (16).…”

Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease

“…Several have evaluated multiple MMP or TIMP SNPs. ( [18][19][20][21][22][23][24][25] ) Some of the studies failed to replicate prior findings ( 15,16,(18)(19)(20)(21)(22)(23)(24)(25), perhaps because of differences in study endpoints, small population sizes, differing study designs (e.g., cohort vs. matched controls), failure to account for epistasis (gene interactions: e.g., MMP-1 and MMP-3), and unmeasured intra-genic allelic heterogeneity.…”

“…( [18][19][20][21][22][23][24][25] This study evaluated the association of SNPs in the genes encoding MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, and TIMP-3 with MI among patients undergoing coronary angiography.…”