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J Am Coll Cardiol, 2003; 41:2130-2137, doi:10.1016/S0735-1097(03)00482-0 © 2003 by the American College of Cardiology Foundation |
* Human Genetics Division, Southampton University Medical School, Southampton, United Kingdom
Cardiothoracic Unit, Southampton General Hospital, Southampton, United Kingdom
Atherosclerosis Research Unit, Karolinska Hospital, Stockholm, Sweden
Manuscript received November 1, 2002; revised manuscript received February 7, 2003, accepted March 20, 2003.
* Reprint requests and correspondence: Dr. Shu Ye, Human Genetics Division, Southampton University Medical School, Duthie Building (808), Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
Shu.Ye{at}soton.ac.uk
OBJECTIVES: The aim of this study was to assess matrix metallloproteinase-3 (MMP3) gene variation in relation to the degree of coronary atherosclerosis and risk of myocardial infarction (MI) in patients with coronary artery disease.
METHODS: In this study, we systematically screened the promoter and coding regions for sequence variants. All polymorphisms identified were analyzed in 1,240 individuals undergoing coronary angiography. Functional analyses of the polymorphisms were carried out with the use of report assays and electrophoretic mobility shift assays.
RESULTS: Six novel polymorphisms were identified. The 6A/6A genotype was associated with greater number of coronary arteries with significant stenosis (odds ratio [OR] 1.52, p = 0.008), whereas the 5A/5A and 5A/6A genotypes were associated with increased risk of MI (OR 2.02 and 1.78, p = 0.016 and 0.032, respectively). A stepwise logistic regression analysis with all polymorphisms taken into account showed that the effect of MI susceptibility was largely attributed to the 5A/6A polymorphism. In a stepwise logistic regression analysis with all haplotypes as independent variables, the most common haplotype (T-5A-A-A-G-A), and two rare haplotypes, all containing the 5A allele, were associated with MI susceptibility. Functional studies showed that the T-5A-A-A-G-A haplotype had a higher promoter activity in macrophages.
CONCLUSIONS: These data indicate that the effect of MMP3 gene variation is attributable to the 5A/6A polymorphism and that individuals carrying the 6A/6A genotype may be predisposed to developing atherosclerotic plaques with significant stenosis, whereas those carrying the 5A allele may be predisposed to developing unstable plaques.
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