Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and Ischemic Stroke: Meta-Analysis

Introduction: The association between ischemic stroke and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR; 677C>T and 1298A>C), endothelial nitric oxide synthase (eNOS; -786T>C, +894G>T, and variable number tandem repeat [VNTR]), phosphodiesterase 4D (PDE4D; SNPs 83 and 87), angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) 235M>T, paraoxonase 1 (PON1) 192Q>R, and apolipoprotein E (ApoE) epsilon 2 epsilon 3 epsilon 4 remains inconclusive. Therefore, this updated meta-analysis aimed to clarify the presumed influence of genetic polymorphisms on ischemic stroke by meta-analyzing the comprehensive coverage of all individual association studies. Methods: All case-control studies published in different languages such as English, Japanese, Korean, Spanish, Chinese, Hungarian, Ukrainian, or Russian were identified from databases. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via fixed-and random-effect models. Sensitivity analysis, heterogeneity test, Hardy Weinberg Equilibrium, and Egger's regression analyses were performed in this study. Results: A total of 490 case-control studies with 138,592 cases and 159,314 controls were included in this meta-analysis. Pooled ORs from all the genetic models indicated that MTHFR 677TT and 1298CC, eNOS +894TT and VNTR, PDE4D SNP 83, ACE DD, AGT 235TT, PON1 192RR, and ApoE epsilon 4 polymorphisms were increasing the risks of ischemic stroke. Nevertheless, PDE4D SNP 87 and eNOS -786T>C polymorphisms are not associated with ischemic stroke risks. Conclusions: Hence, the evidence from this meta-analysis concluded that MTHFR (677C>T and 1298A>C), eNOS (+894G>T and VNTR), PDE4D SNP 83, ACE I/D, AGT 235M>T, PON1 192Q>R, and ApoE epsilon 2 epsilon 3 epsilon 4 polymorphisms predispose individuals to ischemic stroke.