Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.
Pharmacotherapy. 2024 Jun;44(6):416-424. doi: 10.1002/phar.2923. Epub 2024 Apr 30.
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.
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).
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.
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).
CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.
尽管进行了密切监测，但在使用维生素 K 拮抗剂 (VKA) 的患者中，每年仍有 1%-3%发生大出血。参与 VKA 反应的蛋白中的遗传变异可能会影响这种风险。
确定遗传变异（细胞色素 P450 酶 2C9 [CYP2C9] 和 4F2 [CYP4F2]、γ-谷氨酰羧化酶 [GGCX]）与 VKA 使用者大出血的关联，包括维生素 K 环氧化物还原酶复合物亚基 1 (VKORC1) 单独和联合。
在 BLEEDS 队列中建立了病例-队列研究，该队列包括 2012 年至 2014 年间开始使用 VKA 的 16570 名患者。我们选择了在 17613 年随访期间发生的所有 326 例大出血病例和 978 例随机亚组病例。我们确定了 CYP2C9、CYP4F2、GGCX、VKORC1 中的变异，并评估了变异基因型之间的相互作用。通过加权 Cox 回归估计大出血的风险比（95%置信区间 [95%CI]）。
在 256 例病例和 783 例亚组患者中确定了基因型。苯丙香豆素是病例和亚组中最常开的 VKA（分别为 78%和 75%）。大出血患者比亚组患者稍年长。与 CC 等位基因相比，CYP4F2-TT 携带者发生大出血的风险增加 1.6 倍（95%CI 0.9-2.8），但无统计学意义。对于 CYP2C9 和 GGCX 变体，大出血风险约为 1。CYP2C9（弱代谢者）中至少携带两种变异基因型、CYP4F2-TT 和 VKORC1-AA 与大出血风险增加 4.0 倍（95%CI 1.4-11.4）相关，而同时携带 CYP4F2-TT 和 VKORC1-AA 的携带者与 CYP4F2 中的 CC 等位基因携带者和 VKORC1 中的 GG 携带者相比，大出血风险特别增加（风险比 6.7，95%CI 1.5-29.8）。然而，携带多种变体的大出血病例数量较少（分别为 8 例和 5 例患者）。
CYP4F2 多态性与大出血有关，尤其是与 VKORC1 遗传变异相结合时。这些变体可以考虑进一步个体化抗凝治疗。
