Dose-related association of MTHFR 677T allele with risk of ischemic stroke -: Evidence from a cumulative meta-analysis

Background - Data are conflicting concerning ischemic stroke risk associated with a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR 677C -> T), which predisposes to hyperhomocystinemia in vivo. Methods - We performed a systematic review and meta-analysis of published relevant literature. We included cohort, case-control, or cross-sectional studies reporting the frequencies of heterozygous (CT) and homozygous (TT) genotypes in (a) all stroke/TIA (overall group) and (b) imaging-proven ischemic stroke (best-phenotyped group). Results - Among 14 870 subjects, the pooled estimated risk of stroke/TIA associated with the 677T allele increased in a dose-dependent manner (T allele pooled OR 1.17, 95 % CI 1.09 to 1.26, TT genotype pooled OR 1.37, 95 % CI 1.15 to 1.64). An almost-identical relationship was observed when the analysis was restricted to imaging-proven ischemic stroke (T allele pooled OR 1.18, 95 % CI 1.09 to 1.29, TT genotype pooled OR 1.48, 95 % CI 1.22 to 1.8). Conclusion - A graded increase in ischemic stroke risk with increasing MTHFR 677T allele dose was observed, suggesting an influence of this polymorphism as a genetic stroke risk factor and supporting other evidence indicating a causal relationship between elevated homocysteine and stroke.