Lo Faro Valeria, Johansson Therese, Johansson Åsa
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Centre for Women's Mental Health during the Reproductive Lifespan - Womher, Uppsala University, Sweden.
Am J Obstet Gynecol. 2024 Mar;230(3):360.e1-360.e13. doi: 10.1016/j.ajog.2023.09.012. Epub 2023 Sep 19.
More than 150 million women worldwide use oral contraceptives. Women with inherited thrombophilia and carriers of certain thrombophilia gene variants, such as factor V Leiden and the prothrombin, are at an increased risk for venous thromboembolism, especially when combined with oral contraceptive use. Venous thromboembolism is a complex disorder involving many genetic risk factors, and recently, polygenic risk scores have been proposed to capture a significant proportion of the genetic risk of venous thromboembolism.
The aim of this study was to estimate the risk for developing venous thromboembolism when initiating oral contraceptive use (first 2 years) and during continued use among women with a high genetic liability.
We used a prospective study design in which 244,420 participants from the UK Biobank were followed from birth. The effect of oral contraceptive use during the first 2 years and in the remaining years of oral contraceptive use on the risk of developing venous thromboembolism was estimated using a Cox regression with a time-dependent exposure variable. Women were stratified according to their polygenic risk scores and whether they were carriers of factor V Leiden and/or prothrombin variants.
When genetic risk was not considered, an increased risk for venous thromboembolism was observed during the first 2 years of oral contraceptive use (hazard ratio, 3.09; 95% confidence interval, 3.00-3.20) but not during continued use (hazard ratio, 0.92; 95% confidence interval, 0.80-1.05). However, when genetic risk was considered, women in the highest polygenic risk score category had a more pronounced risk of developing a venous thromboembolism during the first 2 years of oral contraceptive use (hazard ratio, 6.35; 95% confidence interval, 4.98-8.09), and a high risk was also observed among factor V Leiden (hazard ratio, 5.73; 95% confidence interval, 5.31-6.17) and prothrombin variant carriers (hazard ratio, 5.23; 95% confidence interval, 4.67 - 5.87). A high polygenic risk score in combination with being a factor V Leiden and prothrombin variant carrier conferred the highest risk for developing a venous thromboembolism during the first 2 years of oral contraceptive use (hazard ratio, 14.8; 95% confidence interval, 9.28-23.6). Women with a high genetic liability also had an increased risk during continued use but it was less pronounced, and the highest risk was conferred to carriers of both factor V Leiden and the prothrombin variant (hazard ratio, 4.93; 95% confidence interval, 3.16-7.7).
Evaluating polygenic risk can identify additional venous thromboembolism risk that is not captured in the commonly investigated genes for inherited thrombophilia. Our results indicate that oral contraceptive use is associated with an increased risk for developing a venous thromboembolism, particularly among women with a high genetic predisposition, and that oral contraceptive use dramatically increases the risk thereof short after initiation of use, which decreases with continued use. This suggests that the polygenic risk score could be used to identify women who are at high risk for developing a venous thromboembolism and advise them on alternative methods of contraception.
全球超过1.5亿女性使用口服避孕药。患有遗传性易栓症的女性以及某些易栓症基因变异的携带者，如凝血因子V莱顿突变型和凝血酶原基因变异型，发生静脉血栓栓塞的风险增加，尤其是在与口服避孕药联合使用时。静脉血栓栓塞是一种涉及多种遗传风险因素的复杂疾病，最近，多基因风险评分已被提出以捕捉静脉血栓栓塞遗传风险的很大一部分。
本研究的目的是评估具有高遗传易感性的女性在开始使用口服避孕药（前2年）和持续使用期间发生静脉血栓栓塞的风险。
我们采用前瞻性研究设计，对英国生物银行的244,420名参与者从出生开始进行随访。使用带有时间依赖性暴露变量的Cox回归估计前2年和口服避孕药使用剩余年份中口服避孕药使用对发生静脉血栓栓塞风险的影响。根据多基因风险评分以及她们是否为凝血因子V莱顿突变型和/或凝血酶原基因变异型携带者对女性进行分层。
在不考虑遗传风险时，观察到在口服避孕药使用的前2年静脉血栓栓塞风险增加（风险比，3.09；95%置信区间，3.00 - 3.20），但在持续使用期间未增加（风险比，0.92；95%置信区间，0.80 - 1.05）。然而，当考虑遗传风险时，多基因风险评分最高类别中的女性在口服避孕药使用的前2年发生静脉血栓栓塞的风险更为明显（风险比，6.35；95%置信区间，4.98 - 8.09），并且在凝血因子V莱顿突变型携带者（风险比，5.73；95%置信区间，5.31 - 6.17）和凝血酶原基因变异型携带者中也观察到高风险（风险比，5.23；95%置信区间，4.67 - 5.87）。多基因风险评分高且同时为凝血因子V莱顿突变型和凝血酶原基因变异型携带者在口服避孕药使用的前2年发生静脉血栓栓塞的风险最高（风险比，14.8；95%置信区间，9.28 - 23.6）。具有高遗传易感性的女性在持续使用期间风险也增加，但不太明显，并且风险最高的是凝血因子V莱顿突变型和凝血酶原基因变异型的双重携带者（风险比，4.9；95%置信区间，3.16 - 7.7）。
评估多基因风险可以识别在遗传性易栓症常见研究基因中未捕捉到的额外静脉血栓栓塞风险。我们的结果表明，口服避孕药使用与发生静脉血栓栓塞的风险增加相关，特别是在具有高遗传易感性的女性中，并且口服避孕药使用在开始使用后短期内显著增加风险，随着持续使用风险降低。这表明多基因风险评分可用于识别发生静脉血栓栓塞风险高的女性，并为她们提供关于替代避孕方法的建议。
