基因多态性与维生素 K 拮抗剂治疗期间的大出血风险:BLEEDS病例队列

IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Pharmacotherapy Pub Date : 2024-04-30 DOI:10.1002/phar.2923
Eleonora Camilleri, Mira Ghobreyal, Mettine H. A. Bos, Pieter H. Reitsma, Felix J. M. Van Der Meer, Jesse J. Swen, Suzanne C. Cannegieter, Nienke van Rein
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引用次数: 0

摘要

背景尽管有严密的监测,但每年仍有1%-3%服用维生素K拮抗剂(VKA)的患者发生大出血。目的确定遗传变异(细胞色素 P450 酶 2C9 [CYP2C9]、4F2 [CYP4F2]、γ-谷氨酰羧化酶 [GGCX])与 VKA 使用者大出血的相关性,包括单独和合并的遗传变异,包括维生素 K 环氧化物还原酶复合物亚基-1 (VKORC1)。方法 在 BLEEDS 队列中建立了一个病例队列研究,该队列包括 16,570 名在 2012 年至 2014 年期间开始使用 VKA 的患者。我们选取了 17613 年随访期间发生的所有 326 例大出血病例和 978 例随机亚队列患者。我们确定了 CYP2C9、CYP4F2、GGCX 和 VKORC1 的变异,并评估了变异基因型之间的相互作用。通过加权 Cox 回归估算了大出血的危险比及 95% 置信区间 (95% CI)。苯丙酮是病例和亚队列中处方最多的 VKA(分别为 78% 和 75%)。大出血患者的年龄略大于亚队列患者。与 CC-等位基因相比,CYP4F2-TT-等位基因与大出血风险增加 1.6 倍(95% CI 0.9-2.8)相关,但无统计学意义。相反,CYP2C9 和 GGCX 变体的大出血风险约为 1。与 CYP4F2 的 CC 等位基因携带者和 VKORC1 的 GG 等位基因携带者相比,CYP2C9(代谢不良)、CYP4F2-TT 和 VKORC1-AA 至少两种变异基因型携带者的大出血风险增加了 4.0 倍(95%CI 1.4-11.4),而 CYP4F2-TT 和 VKORC1-AA 两种变异基因型携带者的大出血风险尤其增加(危险比 6.7,95%CI 1.5-29.8)。结论CYP4F2 多态性与大出血有关,尤其是与 VKORC1 基因变异结合时。这些变异可用于进一步个性化抗凝治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genetic polymorphisms and major bleeding risk during vitamin K antagonists treatment: The BLEEDS case‐cohort
BackgroundMajor 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.AimTo 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).MethodsA 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.ResultsGenotype 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).ConclusionsCYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.
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来源期刊
Pharmacotherapy
Pharmacotherapy 医学-药学
CiteScore
7.80
自引率
2.40%
发文量
93
审稿时长
4-8 weeks
期刊介绍: Pharmacotherapy is devoted to publication of original research articles on all aspects of human pharmacology and review articles on drugs and drug therapy. The Editors and Editorial Board invite original research reports on pharmacokinetic, bioavailability, and drug interaction studies, clinical trials, investigations of specific pharmacological properties of drugs, and related topics.
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