Summary

Homocysteine may have a thrombogenic effect through inhibition of inactivation of factor Va by activated protein C. Because factor V Leiden also leads to resistance of factor V to activated protein C,it would be possible that both factors show interaction for the risk of venous thrombosis. This has been reported in some studies,but not in others.We performed a metaanalysis to investigate a possible interaction between factor V Leiden and hyperhomocysteinemia, including 825 subjects with venous thrombosis and 2,109 controls, for the risk of venous thrombosis. In addition, we assessed a possible interaction between factor V Leiden and MTHFR 677TT genotype (the most common genetic determinant of homocysteine levels), including 2,547 subjects with venous thrombosis and 4,327 controls.We also investigated the interaction effect of factor V Leiden and hy- perhomocysteinemia in a large case-only study using data of the VITRO study, including 2,077 subjects with first-time venous thrombosis.The meta-analysis yielded no evidence for additive or multiplicative interaction between factorV Leiden and hyperhomocysteinemia [relative excess risk due to interaction (RERI) –1.77 (95%CI –8.61 to 5.08) and multiplicative interaction term 0.86 (95%CI 0.35 to 2.14)].The case-only study also showed no interaction effect [0.58 (95%CI 0.29 to 1.16)]. Also the metaanalysis on factor V Leiden and MTHFR 677TT yielded no evidence of interaction;RERI 0.13 (95%CI –3.60 to 3.86) and multiplicative interaction term 1.23 (95%CI 0.72 to 2.11). Both the meta-analyses of published studies and a large case-only study did not show evidence for interaction between factor V Leiden and hyperhomocysteinemia for risk of venous thrombosis.