Influence of the Matrix Metalloproteinase 9 Geners3918242 Polymorphism on Development of Ischemic Stroke: A Meta-analysis

Background

The association between matrix metalloproteinase 9 (MMP-9) gene -1562C/T (rs3918242) polymorphism and the susceptibility of ischemic stroke (IS) has been investigated. However, results were ambiguous and inconsistent. Therefore, we performed this study to better assess the potential relationship between rs3918242 polymorphism and susceptibility risk of IS.

Methods

We included case-control studies concerning the relationship between the rs3918242 polymorphism and IS, and odds ratios with corresponding 95% confidence intervals were used to describe the associations. Furthermore, meta-regression analyses, heterogeneity, cumulative analyses, sensitivity analyses, and publication bias were examined.

Results

A total of 19 studies were included for analysis. Significant associations with the risk of IS were detected for the rs3918242 polymorphism in overall population, Asians, and whites. When available data were stratified by gender, we found a significant correlation with the risk of IS in both males and females. Further subgroup analysis by the subtypes of IS showed that the rs3918242 polymorphism was significantly correlated with the risk of patients with large artery atherosclerosis. When stratified by age, we found that the rs3918242 polymorphism was significantly correlated with the risk of IS in patients both aged ≥65 years and >65 years. Both the diabetes and the nondiabetes subgroups reached significant results, and in an analysis stratified by smoking status, an increased risk of IS was associated with smoking.

Conclusions

The rs3918242 polymorphism may be a susceptible predictor of susceptibility of IS. Further large-scale studies are needed to verify the results of our findings.

Introduction

Stroke is the second most common cause of death in the world as well as the leading cause of long-term disability worldwide.¹ Approximately 80%–90% of strokes are ischemic stroke (IS).2, 3 However, the cause of IS is not well known. Multiple traditional risk factors such as hypertension, diabetes, dyslipidemia, high body mass index (BMI), poor diet, lack of exercise, smoking, alcohol drinking, hyperhomocysteinemia, are associated with a higher risk of IS.⁴ However, these factors can explain only a small part of the cause.⁵ Evidence from twins, families, and animal model studies indicated that gene polymorphisms also exerted influence on IS susceptibility and prognosis.6, 7, 8 Thus, besides traditional risk factors, genetic factors may also contribute to a substantial proportion of the risk and prognosis of IS.9, 10

Much scientific research has indicated that inflammation plays a crucial role in the pathogenesis of stroke.11, 12 Inflammatory mediators can participate in the rapid evolution of arteriosclerosis injury, which leads to arterial plaque rupture and arterial thrombosis.13, 14 Matrix metalloproteinase (MMP) is an inflammatory mediator that belongs to a family of structurally related zinc-binding proteolytic enzymes, which are widely distributed in human tissues. MMPs are produced by nerve cells, microglia, endothelial cells, and astrocytes and play a major role in the physiologic degradation of extracellular matrix during angiogenesis, tissue repair, and tissue morphogenesis.¹⁵ MMP-9 is an important member of the MMP family; among all MMPs, MMP-9 is the most widely investigated enzyme in acute IS, and its expression is rapidly upregulated after cerebral ischemia and hypoxia.16, 17 The human MMP-9 gene is located on the long arm of chromosome 20 (20q12.2–13.1), consisting of 13 exons and 12 introns, and some key functional polymorphisms have been reported,¹⁸ which may lead to the penetration of leucocytes and destabilization of atherosclerotic plaques.¹⁹

The MMP-9 -1562C/T polymorphism (rs3918242) located in the MMP-9 gene promoter has been reported to be associated with higher MMP-9 circulating concentrations.¹⁹ Several studies have been conducted in the past to depict the association between MMP-9 gene -1562C/T polymorphism and IS susceptibility.20, 21, 22 However, the existing findings are controversial and indefinite. This discrepancy might result from the demographic, profound ethnic differences, and small sample sizes. To accurately identify the genetic role of this single nucleotide polymorphism in stroke development, we carried out this systematic meta-analysis to clarify the relationship between the MMM-9 gene -1562C/T polymorphism and IS susceptibility.