Published online before print October 6, 2005, doi: 10.1161/01.RES.0000189302.03303.11
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Submitted on July 11, 2005
Revised on September 12, 2005
Accepted on September 27, 2005
Haplotype Effect of the Matrix Metalloproteinase-1 Gene on Risk of Myocardial Infarction
Eve Pearce ;
From the Human Genetics Division (E.P., A.R.M., C.C., S.Y.), School of Medicine, University of Southampton, United Kingdom; INSERM U525 (D.-A.T), Faculté de Médecine, Hôpital Pitié-Salpêtrière, Paris, France; and Atherosclerosis Research Unit (A.S., A.H., P.E.), King Gustaf V Research Institute, Karolinska Institute, Stockholm, Sweden.
* To whom correspondence should be addressed. E-mail: Shu.Ye{at}soton.ac.uk.
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.
Key words: matrix metalloproteinase • genetics • polymorphism • haplotype analysis • atherosclerosis
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