Common C677T Polymorphism of the Methylenetetrahydrofolate Reductase Gene and the Risk of Venous Thromboembolism: Meta-Analysis of 31 Studies

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Abstract
Background: Although the common 677 C → T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene is implicated in the development of hyperhomocysteinemia, its correlation with venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis of previously published studies to clarify the role of the MTHFR 677 TT homozygous genotype in association with VTE. Methods and Results: Relevant articles were retrieved from a systematic search of Medline and Embase from 1990 to September 2001. Two independent reviewers abstracted data on the characteristics of the cases with VTE and controls without VTE. We pooled the rates of the MTHFR 677 TT genotype in both groups, as well as the odds ratio (OR) of VTE in the presence of the TT versus CC or CT genotypes. In 31 published studies, comprising 4,901 cases and 7,886 controls, the pooled prevalence of the MTHFR 677 TT genotype was slightly higher among cases (14.3%) than controls (11.7%), conferring a borderline degree of heightened risk [pooled OR (ORp) 1.2, 95% confidence interval (CI) 1.1–1.4]. After excluding cases with a classic thrombophilia factor, the pooled prevalence rates of the MTHFR 677 TT genotype among 11 studies were 17.7 and 12.3%, respectively (ORp 1.5, 95% CI 1.2–1.9). Conclusions: The classic MTHFR C677T gene polymorphism is weakly associated with an increased risk of VTE. It is unlikely that the purported relationship between hyperhomocysteinemia and VTE is mediated by this gene defect to a substantial degree, although other undiscovered gene polymorphisms may explain this association. Until more compelling data are made available, we do not recommend that testing for the MTHFR C677T polymorphism be routinely included as part of any clinical thrombophilia assessment.