The genetics of venous thromboembolism A meta-analysis involving ∼120,000 cases and 180,000 controls

We conducted a systematic and comprehensive meta-analysis on all candidate genes to assess their genetic contribution to the aetiology of venous thromboembolism (VTE) (pulmonary embolism and deep venous thrombosis) in all ethnic groups. Electronic databases were searched until and including January 2008 for any candidate gene investigated in VTE. Odds ratios (OR) and 95% confidence intervals (Cl) were determined for each gene disease association using fixed and random effect models. Our meta-analyses included similar to 126,525 cases and 184,068 controls derived from 173 case-control studies, which included 21 genes (28 polymorphisms). Statistically significant associations with VTE were identified for factor V G 169 1 A (OR 9.45; 95% Cl 6.72-13.30, p<0.0001), factor V A4070G (OR 1.24; 95% CI 1.02-1.52,p=0.03), prothrombin G20210A, (OR 3.17; 95% Cl 2.19-3.46, p<0.00001), prothrombin G 1199 1 A, (OR 1.17; 95% Cl 1.07-1.27, p=0.0007), PAI-1 4G/5G, (OR 1.62; 95% Cl 1.22-2.16,p=0.0008),alpha-fibrinogen Thr312Ala (OR 1.37;95% Cl 1.14-1.64, p=0.0008), all in Caucasian populations. MTHFR/C677T in Chinese/Thai populations (OR 1.57; 95% Cl 1.23-2.00, p=0.0003), and ACE I/D in African American populations (OR 1.5; 95% Cl 1.03-2.18, p=0.03) were found to be significantly associated with VTE. Factor XIII Val34Leu (OR 0.80; 95% Cl 0.68-0.94,p=0.007) and beta-fibrinogen 455 G/A (OR 0.84; 95% Cl 0.72-0.97, p=0.02) both showed significantly protective effects. Our work supports a genetic aetiology to VTE disease and provides reliable risk estimates.