A meta- and pooled analysis of the literature on the association between factor V Leiden, prothrombin G20210A and methylentetrahydrofolate reductase C677T variants, their interaction with lifestyle factors, and risk of venous trhomboembolism

Background Three of the five most prescribed genetic tests in Italy are for the thrombophilic polymorphic variants G1691A factor V Leiden (FVL), G20210A prothrombin (PTM) and C677T methylentetrahydrofolate reductase (MTHFR). We evaluated the current evidence on the association between the presence of each of these three variants and the risk of first occurrence of thromboembolic events (VTEs) in adults, their combination and interaction with lifestyle factors. Methods We performed a meta- and pooled analysis of case-control and cohort studies investigating the association between each variant and the occurrence of VTE, published on Pubmed, Embase or Google through June 2009. Authors of the eligible papers were contacted and invited to provide all the available individual data for the pooling, including information on demographic and lifestyle factors. Odds Ratios (ORs) of developing a VTE in the presence of each polymorphic variant, individually and combined with the others, were calculated. A random effect model was used. All statistical analyses were performed using STATA 11.0. Results 37 databases were deemed eligible, corresponding to 10,546 VTE cases and 21,649 controls overall. ORs were calculated after adjusting by age, gender and the three polymorphic variants considered. No significant association was found for MTHFR, whereas FVL and PTM were associated with a higher occurrence of VTE (OR = 3.51; IC95%: 2.53–4.87; OR= 2.47; IC95%: 1.86–3.29, respectively). The stratified analyses showed a stronger effect of FVL and PTM on individuals 45 years (OR = 4.26; IC95%: 2.67–6.81; OR= 2.65; IC95%: 1.84–3.83). Women carriers of the PTM variant are twice as likely than non-carriers to develop a VTE if they do not assume oral contraceptives, and four times as likely if they do (OR = 3.96; IC 95%: 2.43–6.45). Conclusions Testing for FVL and PTM can be useful in identifying individuals at higher risk of VTE, especially in the presence of other risk factors. MTHFR does not appear a risk factor for VTE. It is necessary to implement health technology assessments of genetic tests for an appropriate and cost-effective translation of genetics and genomics applications in public health.