SummaryWe have investigated the interrelationships of plasma PAI-1 activity, the PAI-1 4G/5G polymorphism and risk of myocardial infarction (MI) in the ECTIM study, a case-control study of MI based in Belfast, Lille, Strasbourg and Toulouse. Mean PAI-1 levels in cases were similar across all centres but in controls, levels in the French centres were significantly higher. Only in Belfast were PAI-1 levels higher in cases (11.7AU/ml) than controls (10.5AU/ml). The PAI-1 4G allele frequency was similar in cases and controls (0.55 and 0.54). In all groups, 4G homozygotes had the highest mean plasma PAI-1 level (4G4G vs 5G5G; cases overall: 14.2 vs 12.1 AU/ml; controls overall: 15.0 vs 12.6AU/ml), with the heterozygotes generally intermediate. The data from Belfast are consistent with the literature implicating PAI-1 level as an MI risk factor. In ECTIM, the PAI-1 4G/5G polymorphism is not a genetic risk factor for MI but is associated with PAI-1 activity. Thus homozygosity for the 4G allele may predispose to elevated PAI-1 and impaired fibrinolysis, perhaps requiring interaction with other genetic or environmental factors to influence MI risk.

BACKGROUND Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden,FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. METHODS We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). RESULTS We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95% confidence intervals [CI]: 0.98–1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR=4.22; 95% CI: 3.35–5.32; and OR=2.79;95% CI: 2.25–3.46, respectively), in double hterozygotes (OR=3.42; 95%CI 1.64-7.13), and in homozygous FVL or PT20210A (OR=11.45; 95%CI: 6.79-19.29; and OR: 2.79; 95%CI: 2.25 – 3.46, respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤45 years (p-value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). CONCLUSIONS In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

SummaryThrombin activatable fibrinolysis inhibitor (TAFI), a recently described inhibitor of fibrinolysis, has been hypothesized as playing a role in atherothrombosis. However, the evidence from retrospective studies, which have evaluated the role of TAFI in vascular risk, is conflicting.In a prospective cohort (the PRIME Study) of nearly 10 000 apparently healthy men recruited in France (Lille, Strasbourg, Toulouse) and Northern Ireland (Belfast), we measured baseline plasma concentration of TAFI antigen among 143 participants (81 from France and 62 from Ireland) who subsequently developed angina pectoris and among 286 age-matched participants who remained free of disease during the 5 years of follow-up. Genotyping of the Ala147Thr polymorphism located in the TAFI gene was performed using an allele specific PCR. In France, mean levels of TAFI were significantly higher at baseline among men who subsequently developed angina pectoris compared with their control subjects (119 versus 107 %; p = 0.02). The risk of future angina pectoris increased with increasing tertiles of TAFI (p = 0.02), such that men in the highest tertile at study entry had a 5-fold higher relative risk than those in the lowest tertile (95% confidence interval, 1.38 to 18.58) after controlling for the conventional cardiovascular risk factors. No such difference was observed in Northern Ireland. In France, Thr/Thr carriers of the Ala147Thr polymorphism were significantly more frequent in cases than in controls (p = 0.01) leading to a relative risk of angina pectoris of 2.7 (95%CI 1.2-5.8).Increase in plasma TAFI antigen levels is a risk factor for angina pectoris in France. Genotyping for the Ala147Thr polymorphism seems to be a reliable tool to assess the risk mediated by TAFI.

Objectives To investigate VTE risk in relation to age at menopause, age at menarche, parity, bilateral oophorectomy and time since menopause, as well as any interaction with randomized HT assignment among postmenopausal women. Methods Using pooled data from the Women’s Health Initiative HT clinical trials including 27,035 postmenopausal women ages 50 to 79 years with no history of VTE, we assessed the risk of VTE in relation to age at menopause, age at menarche, parity, bilateral oophorectomy and time since menopause by Cox proportional hazard models. Linear trends, quadratic relationships and interactions of reproductive life characteristics with HT on VTE risk were systematically tested. Results During the follow-up, 426 women reported a first VTE, including 294 nonprocedure-related events. No apparent interaction of reproductive life characteristics with HT assignment on VTE risk was detected and there was any significant association of VTE with age at menarche, age at menopause, parity, oophorectomy or time since menopause. However, analyses restricted to nonprocedure-related VTE showed a U-shaped relationship between age at menopause and thrombotic risk that persisted after multivariable analysis (p<0.01). Compared to women aged 40 to 49 years at menopause, those with early menopause (age<40 years) or with late menopause (age>55 years) had a significant increased VTE risk (HR=1.8;95%CI:1.2–2.7 and HR=1.5;95%CI:1.0–2.4, respectively). Conclusion Reproductive life characteristics have little association with VTE and do not seem to influence the effect of HT on thrombotic risk among postmenopausal women. Nevertheless, early and late onset of menopause might be newly identified risk factors for nonprocedure-related VTE.