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No Association Between the Common MTHFR 677CT Polymorphism and Venous Thrombosis

Results From the MEGA Study

Irene D. Bezemer, MSc; Carine J. M. Doggen, PhD; Hans L. Vos, PhD; Frits R. Rosendaal, MD

Arch Intern Med. 2007;167(5):497-501.

Background  Increased homocysteine levels are related to the occurrence of venous thrombosis, but whether this relation is causal is unclear. The T-variant of the common methylenetetrahydrofolate reductase (MTHFR) 677CT polymorphism mildly increases homocysteine levels. Meta-analyses have demonstrated a weak effect of the MTHFR 677TT genotype on risk but are sensitive to selective publication of positive results. The aim of the present study was to evaluate the effect of the MTHFR genotype on the risk of venous thrombosis, overall and in subgroups of known risk factors, in a single large study.

Methods  In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA Study), a population-based case-control study, we collected DNA from 4375 patients with a first deep vein thrombosis of the leg or pulmonary embolism and from 4856 control subjects. Information about risk factors for venous thrombosis was obtained from questionnaires.

Results  MTHFR 677CT was not associated with the risk of venous thrombosis (odds ratio [95% confidence interval], 0.99 [0.91-1.08] for the CT genotype and 0.94 [0.81-1.08] for the TT genotype). Stratification by known risk factors for venous thrombosis provided no evidence of an association in specific groups.

Conclusions  In a single large study, MTHFR 677CT was not associated with the risk of venous thrombosis, and the narrow confidence interval excludes even a small effect. Therefore, mildly elevated homocysteine levels as a result of MTHFR 677TT do not seem to cause venous thrombosis. There is no rationale for measuring the MTHFR 677CT variant for clinical purposes.

Author Affiliations: Department of Clinical Epidemiology (Ms Bezemer and Drs Doggen and Rosendaal), and Hemostasis and Thrombosis Research Center, Department of Hematology (Drs Vos and Rosendaal), Leiden University Medical Center, Leiden, the Netherlands.

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