Genetic polymorphism c.1562C>T of the MMP-9 is associated with macroangiopathy in type 2 diabetes mellitus

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Abstract

Objective

To determine whether the matrix metalloproteinase-9 (MMP-9) c.1562C>T polymorphism has an effect on the plasma MMP-9 levels and the macroangiopathic complications in type 2 diabetes mellitus (T2DM).

Methods

The genotypes and allelic frequencies of the MMP-9 c.1562C>T were examined with polymerase chain reaction and restriction fragment length polymorphism in 320 patients with T2DM and 160 unrelated healthy subjects. The plasma concentrations of MMP-9 were determined in all subjects.

Results

The mean plasma concentrations of MMP-9 of patients with T2DM were significantly higher than that of controls and the plasma levels of MMP-9 were higher in diabetic patients with macroangiopathy than in patients without macroangiopathy (P < 0.05). The genotype (CC, CT, and TT) distribution of c.1562C>T polymorphism of the MMP-9 gene was 60.0%, 31.3%, and 8.8% in diabetic patients with macroangiopathy, 76.3%, 21.3%, and 2.5% in patients without macroangiopathy, and 77.5%, 21.3%, 1.3% in controls, respectively, a significant difference was found between diabetic patients with and without macroangiopathy (P < 0.05). The frequency of the allele T was higher in patients with macroangiopathy than in patients without macroangiopathy (24.4% vs 13.1%; P < 0.05). Moreover, the plasma MMP-9 levels were markedly higher in patients with TT genotype than those with CC or CT genotype in patients with macroangiopathy (P < 0.05).

Conclusion

The MMP-9 c.1562C>T gene polymorphism associated with a predisposition to increased plasma MMP-9 levels could constitute a useful predictive marker for diabetic macroangiopathy.

Introduction

Type 2 diabetes mellitus (T2DM) is strongly associated with elevated mortality and morbidity from atherosclerotic vascular disease manifesting as coronary heart disease, cerebrovascular disease, and peripheral vascular disease [1], [2]. Diabetic macroangiopathy, manifested by atherosclerosis of coronary arteries, cerebral arteries, and large arteries of the lower extremities, is the major cause of mortality and significant morbidity [3]. Predictors of susceptibility for development of macroangiopathy in diabetic subjects would help focus our treatment strategies.

Matrix metalloproteinase-9 (MMP-9) is one of a set of zinc-dependent endopeptidases capable of degrading components of the extracellular matrix (ECM) [4]. The MMP-9 gene has a C-to-T promoter polymorphism at position −1562, which affects transcription and leads to promoter low-activity (C/C) and high-activity (C/T, T/T) genotypes [5]. MMP-9 has three repetitive type II fibronectin domains, which allow it to bind to ECM components, such as gelatin, collagen, and laminin. Increased expression of this enzyme is seen in some neoplastic, cardiovascular, and respiratory diseases [6]. Recent studies revealed that the plasma level of MMP-9 was of both diagnostic and prognostic significance in coronary artery diseases and renal diseases [7], [8], [9], [10]. MMP-9 has recently been identified in human atherosclerotic lesions [11], [12]. It is active against denatured collagens and type IV, V, and XI collagens in addition to the proteoglycans and elastin also found in atherosclerotic lesions [13], [14].

No data are as yet available on the impact of the MMP-9 genotypes at the vessel-wall level in respect to the atherosclerotic plaque rupture and thrombosis. Nor has it hitherto been sought to establish whether MMP-9 genotypes affect development and progression of diabetic macroangiopathy. In the present study, we investigated the association between MMP-9 c.1562C>T polymorphism and the macroangiopathy in T2DM.

Section snippets

Materials and methods

Study subjects. The study was approved by the Clinical Research Ethics Committee of Harbin Medical University, and all subjects gave written informed consent. Macroangiopathy was diagnosed by the presence of cardiovascular disease or cerebrovascular disease and peripheral vascular disease. Cardiovascular disease was defined as a history of myocardial infarction, angina pectoris or ischemic heart disease, ongoing treatment with drugs prescribed for cardiovascular disease, or the presence of a

Association of the MMP-9 c.1562C>T polymorphism with diabetic macroangiopathy

The relationship between distribution frequency of genotypes and alleles of MMP-9 was shown in Table 1. The genotype frequency of the c.1562C>T polymorphism of the MMP-9 gene were as follows: the genotype (CC, CT, and TT) distribution of c.1562C>T polymorphism of the MMP-9 gene was 60.0%, 31.3%, and 8.8% in diabetic patients with macroangiopathy, 76.3%, 21.3%, and 2.5% in diabetic patients without macroangiopathy, and 77.5%, 21.3%, and 1.3% in controls, respectively. The genotype frequency for

Discussion

In the present study, we raised the question of whether the polymorphism of the MMP-9 gene may be associated with diabetic macroangiopathy. Specifically, we hypothesized that the allele frequencies of the different polymorphisms in diabetic patients might be different from those in nondiabetic subjects and that the different polymorphisms could be related to various forms of macroangiopathy and its risk factors in patients with type 2 diabetes. Our results suggested that genetic polymorphism

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    These authors contributed equally to this study.

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