Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study.

Moderate hyperhomocysteinaemia is a risk factor for venous thromboembolism. We do not know whether this risk depends on homocysteine itself or on components of the homocysteine remethylation pathway, such as methylfolate. We did a case-control study to analyse the relation between the major components of the homocysteine remethylation pathway and risk of venous thromboembolism.We measured concentrations of homocysteine, methionine, and folate in plasma, total folate and methylfolate in red-blood cells, and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotype and other known risk factors for venous thromboembolic disease in 243 patients with deep vein thrombosis or pulmonary embolism and controls matched for sex and age.Concentrations in plasma of homocysteine differed significantly between cases and controls. We noted a strong concentration-dependent association between concentrations of methylfolate in red-blood cells and risk of venous thromboembolism. The adjusted conditional odds ratio ranged from 1.0 for methylfolate 249 microg/L or greater to 7.1 (3.2-15.8) for methylfolate 141 microg/L or less. Methionine concentrations below the median were also independently associated with raised risk of venous thromboembolic disease, as were established risk factors such as high body-mass index, history of cancer, family history of thromboembolism, oral contraceptive use, and factor V Leiden mutation. Furthermore, the association between concentrations of methylfolate in red-blood cells and risk of thromboembolism varied according to MTHFR C677T genotype.Measurement of methylfolate concentrations in red-blood cells might help to identify people at risk of venous thromboembolism.