Haplotype effect of the matrix metalloproteinase-1 gene on risk of myocardial infarction.
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.
Pearce
Eve
E
Human Genetics Division, School of Medicine, University of Southampton, United Kingdom.
Tregouet
David-Alexandre
DA
Samnegård
Ann
A
Morgan
Angharad R
AR
Cox
Charles
C
Hamsten
Anders
A
Eriksson
Per
P
Ye
Shu
S
D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000201:enzymology; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012306:Risk
D009687:Nuclear Proteins; D020781:Matrix Metalloproteinase 1