Title
Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis
Author
Zhang, B.
Ye, S.
Herrmann, S.M.
Eriksson, P.
de Maat, M.
Evans, A.
Arveiler, D.
Luc, G.
Cambien, F.
Hamsten, A.
Watkins, H.
Henney, A.M.
TNO Preventie en Gezondheid
Publication year
1999
Abstract
Background - Gelatinase B, a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the connective tissue remodeling processes associated with atherogenesis and plaque rupture. This study tested the hypothesis that sequence variation in the promoter region of the gelatinase B gene influences its expression, predisposing individuals carrying certain genetic variants to more severe atherosclerosis. Methods and Results - Single-strand conformation polymorphism analysis was carried out to search the promoter region of the gene encoding gelatinase B for 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. Transient 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 repressor protein to the C allelic promoter. A sample of 584 male patients with myocardial infarction and 645 age-matched male healthy control subjects were genotyped. The allele frequencies were not significantly different between the cases and control subjects. However, in 374 patients with available angiographic data, 26% of those carrying 1 or 2 copies of the T allele had >50% stenosis in 3 coronary arteries, whereas only 15% of C/C homozygotes had triple-vessel disease. Conclusions - These data suggest that this functional genetic variation influences gelatinase B gene promoter activity in an allele-specific manner and has an effect on atherosclerotic phenotype.
Subject
Biology
Atherosclerosis
Genetics
Metalloproteinases
Molecular biology
Adult
Base Sequence
Collagenases
Coronary Angiography
Coronary Arteriosclerosis
Humans
Male
Matrix Metalloproteinase 9
Middle Aged
Molecular Sequence Data
Polymorphism, Genetic
Promoter Regions (Genetics)
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TNO identifier
234999
ISSN
0009-7322
Source
Circulation, 99 (14), 1788-1794
Document type
article