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.
This work was supported by the British Heart Foundation, London (grants PG/98183 and PG/98192), the University of Southampton School of Medicine (PhD studentship to S.B.), the Swedish Medical Research Council, Stockholm (12660), and the King Gustaf V and Queen Victorias Foundation, Stockholm.
