A Functional Single Nucleotide Polymorphism -1562C>T in the Matrix Metalloproteinase-9 Promoter Is Associated With Type 2 Diabetes and Diabetic Foot Ulcers

Abstract

Impaired neovascularization is the hallmark of type 2 diabetes, which results in various macro- and microvascular complications and the development of foot ulcerations later in life. Matrix metalloproteinases (MMPs) are the key enzymes which influence matrix remodeling. Here, we aim to investigate that whether single nucleotide polymorphism (SNP -1562C>T) (rs3918242) in the promoter region of MMP-9 gene, which alters the transcriptional activity of MMP-9 is associated with type 2 diabetes and diabetic foot ulcers (DFUs). This case-control study was composed of 730 individuals, out of which 463 patients were with type 2 diabetes mellitus (T2DM) and 267 were nondiabetic healthy controls (non-DM controls). T2DM patients were subclassified as 149 cases without any secondary complications (T2DMNSC), 110 with DFUs, 204 T2DM patients having one or the other secondary complications. Genotyping for -1562C>T SNP in MMP-9 gene was done by polymerase chain reaction-restriction fragment length polymorphism method and sequencing. SNP -1562C>T of MMP-9 gene showed a significant association with T2DM and DFU. The allele distribution differed significantly between patients and normal control group (odds ratio = 1.82, P = .00005, 95% confidence interval = 1.36-2.42 for T2DM vs control and odds ratio = 2.112, P = .00048, 95% confidence interval = 1.38-3.126 for DFU vs control) indicating strong association of SNP -1562C>T of MMP-9 gene with T2DM and DFU in an Indian population. SNP -1562C>T in the promoter of the MMP-9 gene results in increased expression at the level of the transcription. To the best of our knowledge, this is the first report that suggests that SNP -1562C>T in the promoter of the MMP-9 gene is associated with T2DM and DFU. An increased MMP-9 production from high expressing T allele may promote matrix degradation.