Published Online
on June 9, 2005

A more recent version of this article appeared on July 1, 2005

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Submitted on February 7, 2005
Revised on April 1, 2005
Accepted on April 7, 2005

Dose-Related Association of MTHFR 677T Allele With Risk of Ischemic Stroke. Evidence From a Cumulative Meta-Analysis

Simon Cronin MB, MRCPI; Karen L. Furie MD, MPH; and Peter J. Kelly MD, MS, MRCPI^*

From the Neurovascular Clinical Science Unit (S.C., P.J.K.), Department of Neurology, Mater Misericordiae University Hospital, Dublin, Ireland; and the Stroke Service (K.L.F., P.J.K.), Department of Neurology, Massachusetts General Hospital, Boston.

^* To whom correspondence should be addressed. E-mail: pjkelly{at}partners.org.

Background--Data are conflicting concerning ischemic stroke risk associated with a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR 677CT), 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.

Key words: cerebrovascular disorders • folic acid • gene mutation • homocysteine

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