Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies


M. den Heijer, Department of Endocrinology (531), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Tel.: +31 24 3614599; fax: +31 24 3618809; e-mail: m.denheijer@endo.umcn.nl


Summary. Context: It has been suggested that elevated total plasma homocysteine levels are associated with the risk of venous thrombosis. Objective: To assess the relationship of homocysteine and the MTHFR 677TT genotype and the risk of venous thrombosis by conducting a meta-analysis of all relevant studies. Data sources and selection: Studies (case–control or nested case–control) were identified by searches of electronic literature for relevant reports published before July 2003 on homocysteine and the MTHFR 677TT genotype and venous thrombosis as an end-point, by hand-searching reference lists of original articles (including meta-analyses) on this topic and by contact with investigators in the field. Data extraction: A meta-analysis of 24 retrospective (n = 3289 cases) and three prospective studies (n = 476 cases) was carried out to examine the association of homocysteine with venous thrombosis. A meta-analysis of 53 studies (n = 8364 cases) of the MTHFR 677TT genotype (that increases homocysteine) was carried out to assess if this association is causal. Data synthesis: A 5 µmol L−1 higher measured homocysteine level was associated with a 27% (95% CI: 1–59) higher risk of venous thrombosis in prospective studies and a 60% (95% CI: 10–134) higher risk in retrospective studies. The 677TT genotype was associated with a 20% (95% CI: 8–32) higher risk of venous thrombosis compared with the 677CC genotype. In contrast with non-American studies, the 677TT genotype had no effect on venous thrombosis in North America, due probably to the higher intake of folate and riboflavin in North America. Conclusion: This meta-analysis of prospective and retrospective studies demonstrates a modest association of homocysteine with venous thrombosis. The elevated risk associated with the MTHFR 677TT genotype provides some support for causality.