Genetic variation, gene-expression and circulating levels of matrix metalloproteinase-9 in patients with stable coronary artery disease.

BACKGROUND

Mediators involved in atherosclerosis and plaque rupture may have importance as risk markers for coronary artery disease (CAD). We have investigated the influence of matrix metalloproteinase (MMP)-9 genetic variations on gene- and protein expression in stable CAD patients.

METHODS

The promoter -1562C/T and exon 6 R279Q A/G polymorphisms were determined in 1001 patients with angiographically verified stable CAD and in 204 healthy controls. Genotype and gene-expression were determined by real-time PCR. Serum levels of MMP-9 and its inhibitor TIMP-1were measured immunologically and by zymography (MMP-9 activity).

RESULTS

None of the polymorphisms associated with the presence of CAD, myocardial infarction or type 2 diabetes, whereas the variant allele of the R279Q polymorphism associated with hypertension (adjusted p=0.015). The T- and G alleles associated with lower and higher mRNA levels, respectively (p<0.005 both), also shown in an experimental ex-vivo LPS stimulated model. T-allele carriers had higher concentrations of MMP-9 (adjusted p=0.032) and the GG genotype induced lower MMP-9 gelatinolytic activity (p=0.01). Higher MMP-9 gene-expression and TIMP-1 levels were observed in patients with previous myocardial infarction, the latter also was elevated in diabetics (<0.05, all).

CONCLUSION

The investigated MMP-9 polymorphisms influenced gene- and protein expression differently and the R279Q polymorphism associated significantly with hypertension.