Allele-Specific Regulation of Matrix Metalloproteinase-12 Gene Activity Is Associated With Coronary Artery Luminal Dimensions in Diabetic Patients With Manifest Coronary Artery Disease

Abstract

Both the processes of atherosclerosis and plaque rupture are indicated to be influenced by matrix metalloproteinase (MMP) activity. We therefore searched for common functional variation in the matrix metalloelastase (MMP-12) gene locus that may be implicated in coronary artery disease. Single-strand conformation polymorphism analysis of DNA from healthy individuals detected a common polymorphism within the MMP-12 gene promoter (an A-to-G substitution at position -82). The frequency of the G allele was 0. 19. The polymorphism influences the binding of the transcription factor activator protein-1 (AP-1) in electromobility shift assay. A higher binding affinity of AP-1 to the A allele was associated with higher MMP-12 promoter activity in vitro in transient transfection studies in U937 and murine lung macrophage (MALU) cells. Phorbol 12-myristate 13-acetate (PMA) and insulin, 2 known activators of AP-1, increased the binding of AP-1 to the MMP-12 promoter, with higher affinity for the A allele. In transfection experiments, both the A and the G alleles responded to insulin and PMA, the A allele showing higher promoter activity than the G allele. Furthermore, Western blot analysis demonstrated that insulin increased MMP-12 protein production. To analyze whether the -82 A/G polymorphism is associated with coronary artery disease, 367 consecutive patients who underwent percutaneous transluminal coronary angiography with stent implantation were genotyped. In patients (n=71) with diabetes, the A allele was associated with a smaller luminal diameter. In conclusion, a common functional polymorphism within the MMP-12 promoter influences coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.

Role of genetic polymorphisms in tumour angiogenesis

“…The T allele of the C-1562T polymorphism demonstrates increased transcriptional activity (Ye, 2000) and is associated with severity of coronary atherosclerosis (Zhang et al, 1999b). Another polymorphism detected in MMP-12 (782 A4G), also overexpressed in tumours, regulates MMP-12 expression (Jormsjo et al, 2000).…”

Functional polymorphism in the promoter region of the gelatinase B gene in relation to coronary artery disease and restenosis after percutaneous coronary intervention

“…Three functional polymorphisms of MMPs are known to be related to coronary artery disease, i.e., MMP-3, MMP-9, and MMP-12 (Ye et al 1995;Terashima et al 1999;Zhang et al 1999;Jormsjo et al 2000).…”

Functional single nucleotide polymorphisms of matrix metalloproteinase 7 and 12 genes in idiopathic recurrent spontaneous abortion

“…Expression of the MMP12 gene was found to be upregulated in deciduas of women with IRSA compared to controls [12]. The A allele of the MMP12 -82 A/G SNP enhances the binding of the transcription factor activator protein 1, increasing promoter activity [45]. It has been suggested that the G allele is associated with epithelial ovarian carcinoma [46], whereas the AA genotype possibly contributes to a higher risk of disseminated colorectal carcinoma, chronic obstructive pulmonary disease, and systemic sclerosis [31,35,36].…”