Abstract：
BACKGROUND: Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.
OBJECTIVE: To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1).
METHODS: A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.
RESULTS: Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).
CONCLUSIONS: CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.
OBJECTIVE: To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1).
METHODS: A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.
RESULTS: Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).
CONCLUSIONS: CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.
摘要：
背景：每年有1%-3%的维生素K拮抗剂（VKAs）患者发生大出血，尽管密切监测。参与VKA反应的蛋白质中的遗传变异可能会影响这种风险。
目的：确定遗传变异的关联（细胞色素P450酶2C9[CYP2C9]和4F2[CYP4F2]，γ-谷氨酰羧化酶[GGCX]）在VKA使用者中出现大出血，分开和组合，包括维生素K环氧化物还原酶复合物亚基1（VKORC1）。
方法：在BLEEDS队列中建立了一项病例队列研究，其中包括2012年至2014年期间启动VKAs的16,570名患者。我们选择了在17,613年随访期间发生的所有326例大出血病例和978例患者的随机子队列。我们确定了CYP2C9，CYP4F2，GGCX，VKORC1并评估了变异基因型之间的相互作用。通过加权Cox回归评估具有95%置信区间(95%CI)的大出血风险比。
结果：在256例和783个亚组成员中确定了基因型。Phenprocoumon是两种情况和亚组的最常用的VKA(78%和75%，分别)。大出血患者比亚队列患者年龄稍大。与CC等位基因相比，CYP4F2-TT载体与大出血风险增加1.6倍（95％CI0.9-2.8）相关。尽管没有统计学意义。对于CYP2C9和GGCX变体，主要的出血风险是团结。在CYP2C9（代谢不良）中携带至少两种变异基因型，CYP4F2-TT,VKORC1-AA与风险增加4.0倍（95CI1.4-11.4）相关，而与CYP4F2和VKORC1中的GG等位基因携带者相比,CYP4F2-TT和VKORC1-AA携带者的大出血风险特别增加(风险比6.7,95%CI1.5-29.8).然而,多变异携带者的大出血病例数很少(8例和5例，分别)。
结论：CYP4F2多态性与大出血有关，特别是与VKORC1遗传变异结合。这些变体可以被认为是进一步个性化抗凝治疗。
目的：确定遗传变异的关联（细胞色素P450酶2C9[CYP2C9]和4F2[CYP4F2]，γ-谷氨酰羧化酶[GGCX]）在VKA使用者中出现大出血，分开和组合，包括维生素K环氧化物还原酶复合物亚基1（VKORC1）。
方法：在BLEEDS队列中建立了一项病例队列研究，其中包括2012年至2014年期间启动VKAs的16,570名患者。我们选择了在17,613年随访期间发生的所有326例大出血病例和978例患者的随机子队列。我们确定了CYP2C9，CYP4F2，GGCX，VKORC1并评估了变异基因型之间的相互作用。通过加权Cox回归评估具有95%置信区间(95%CI)的大出血风险比。
结果：在256例和783个亚组成员中确定了基因型。Phenprocoumon是两种情况和亚组的最常用的VKA(78%和75%，分别)。大出血患者比亚队列患者年龄稍大。与CC等位基因相比，CYP4F2-TT载体与大出血风险增加1.6倍（95％CI0.9-2.8）相关。尽管没有统计学意义。对于CYP2C9和GGCX变体，主要的出血风险是团结。在CYP2C9（代谢不良）中携带至少两种变异基因型，CYP4F2-TT,VKORC1-AA与风险增加4.0倍（95CI1.4-11.4）相关，而与CYP4F2和VKORC1中的GG等位基因携带者相比,CYP4F2-TT和VKORC1-AA携带者的大出血风险特别增加(风险比6.7,95%CI1.5-29.8).然而,多变异携带者的大出血病例数很少(8例和5例，分别)。
结论：CYP4F2多态性与大出血有关，特别是与VKORC1遗传变异结合。这些变体可以被认为是进一步个性化抗凝治疗。
