Association between Tumor Necrosis Factor-α (-238G/A and -308G/A) Gene Polymorphisms and Risk of Ischemic Stroke: A Meta-Analysis

Tumor necrosis factor-α (TNF-α) is a proinflammatory pleiotropic cytokine which may contribute to the initiation and progression of ischemic stroke (IS). Thus far, numerous studies have been performed to examine the association between -238G/A (rs361525) and -308G/A (rs1800629) polymorphisms in the promoter regions of the TNF-α gene and susceptibility to IS, but results are still conflicting. The aim of this meta-analysis is to provide a relatively comprehensive account of the association between TNF-α -238G/A and -308G/A gene polymorphisms and susceptibility to IS. A literature search for eligible candidate gene studies published before April 20, 2015, was conducted in the PubMed, Medline, EMBASE and Google Scholar databases. The following combinations of main keywords were used: ('Tumor Necrosis Factor-Alpha' or 'TNF-α') and ('ischemic stroke' or 'cerebral infarction' or 'IS') and ('genetic polymorphism' or 'single nucleotide polymorphisms' or 'SNP'). Fixed- or random-effect models were used to estimate the pooled odds ratio (OR) and 95% confidence interval (CI). Meta-analysis was carried out by using RevMan 5.3 software. For TNF-α -238G/A gene polymorphism, 7 case-control studies with a total of 1,846 IS patients and 1,905 controls showed a significant association with susceptibility to IS under a dominant model (AA + GA vs. GG; OR, 1.40; 95% CI, 1.11-1.76; p value 0.004). For TNF-α -308G/A gene polymorphism, 16 case-control studies with a total of 5,651 IS patients and 5,792 controls showed a significant protective association with susceptibility to IS under a dominant model (AA + GA vs. GG; OR, 0.78, 95% CI, 0.63-0.97; p value 0.03). Our meta-analysis shows that TNF-α -238G/A gene polymorphism is more likely to be associated with the risk of IS in Caucasian populations as compared to Asian populations. However, TNF-α -308G/A gene polymorphism is more likely to be protective against IS in Asian populations as compared to Caucasian populations. Further large, well-designed prospective epidemiological studies are needed to confirm these findings.