Genetic risk factors for venous thrombosis in women using combined oral contraceptives: update of the PILGRIM study
Résumé
Identifying women at risk of venous thrombosis (VT) under combined oral contraceptives (COC) is a major public health issue. The aim of this study was to investigate in COC users the impact on disease of genetic polymorphisms recently identified to associate with VT risk in the general population. Nine polymorphisms located on KNG1, F11, F5, F2, PROCR, FGG, TSPAN and SLC44A2 genes were genotyped in a sample of 766 patients and 464 controls as part of the PILGRIM (PILl Genetic Risk Monitoring) study. Cases were women who experienced an episode of documented VT during COC use, while controls were women with no history of VT using COC at the time of inclusion. Among the studied polymorphisms, only F11 rs2289252 was significantly associated with VT. The F11 rs2289252‐A allele was associated with a 1.6‐fold increased risk of VT (p < 0.0001). Besides, the combination of the rs2289252‐A allele with non‐O blood group, present in 52% of the cohort, was associated with an odds ratio of 4.00 (2.49–6.47; p < 10 −4). The consideration of this genetic risk factor could help to better assess the risk of VT in COC users. In women, the overall incidence of venous thrombosis (VT) is about 1.2 per 1000 person‐ years 1; this incidence being lower in women of reproductive age, with an estimate ranging between 0.4 and 0.6 per 1000 person‐years 1. The use of combined oral contraceptive (COC) is a major established risk factor for VT in women of reproductive age. The relative risk for COC use is about 3–6. It is well known that this risk depends on two major factors: the progestogen and the ethinyl estradiol dosage 2. It is estimated that more than 100 million women worldwide are using COC, making the impact of COC use on VT risk and public health of major importance 3. In France, 20 young women die annually of pulmonary embolism (PE) as a consequence of COC use 4. Furthermore, young and middle‐aged women with a personal history of VT have a 2.3‐fold increased risk of mortality 5. Besides, among survivors, 25–50% will have lasting debilitating health problems such as post‐thrombotic syndrome, severely hampering mobility and quality of life 6. Chronic thromboembolic pulmonary hypertension occurs in about 3% PE patients 7. Oral contraceptives and inherited thrombophilic defects (i.e. factor V Leiden and prothrombin mutations, deficiencies of protein C, protein S or antithrombin) are known to interact synergistically to increase the risk of VT 8. Very recently, we have found that the ABO blood group, an increasingly recognized risk factor for VT in the general population, was also associated with the risk of VT in COC users. In the PILGRIM (Pill Genetic Risk Monitoring) study, we observed that, under COC use, women of non‐O blood group displayed a 1.85‐fold increased risk of VT compared with O blood group carriers 9. Last year, the International VENous Thrombosis (INVENT) consortium presented the results of the first international meta‐analysis of genome‐wide association studies for VT in the general population 10. This project led to the identification of two unsuspected susceptibility
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