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).


CONCLUSIONS
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.
Cronin
Simon
S
Neurovascular Clinical Science Unit, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland.
Furie
Karen L
KL
Kelly
Peter J
PJ
D000328:Adult; D000368:Aged; D000483:Alleles; D002545:Brain Ischemia; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D012306:Risk; D020521:Stroke / Q000175:diagnosis* / Q000235:genetics*
D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)