Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis

Background-Gelatinase B, a matrix metalloproteinase that has proteolytic ac tivity against connective tissue proteins, has been suggested to be importa nt in the connective tissue remodeling processes associated with atherogene sis and plaque rupture. This study tested the hypothesis that sequence vari ation in the promoter region of the gelatinase B gene influences its expres sion, predisposing individuals carrying certain genetic variants to more se vere atherosclerosis. Methods and Results-Single-strand conformation polymorphism analysis was ca rried out to search the promoter region of the gene encoding gelatinase B f or naturally occurring genetic variation, As a result, an unreported common polymorphism was detected, which arose from a cytosine (C) to thymidine (T ) transition at position -1562 relative to the start of transcription. Tran sient transfection experiments and DNA-protein interaction assays indicated that the T allele had a higher promoter activity than the C allele, which appeared to be due to preferential binding of a putative transcription repr essor protein to the C allelic promoter. A sample of 584 male patients with myocardial infarction and 645 age-matched male healthy control subjects we re genotyped. The allele frequencies were not significantly different betwe en the cases and control subjects. However, in 374 patients with available angiographic data, 26% of those carrying I or 2 copies of the T allele had >50% stenosis in 3 coronary arteries, whereas only 15% of C/C homozygotes h ad triple-vessel disease. Conclusions-These data suggest that this functional genetic variation influ ences gelatinase B gene promoter activity in an allele-specific manner and has an effect on atherosclerotic phenotype.