Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients.
Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients.
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DOI：
10.3389/fphar.2022.1007113
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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背景：房颤（AF）是缺血性卒中的主要原因，治疗的重点是通过抗凝来降低这种风险。直接口服抗凝剂（DOACs）是一线指南推荐的治疗方法，因为它们在预防房颤相关卒中方面与华法林一样有效且总体上更安全。尽管与华法林相比，DOACs患者出血较少，但出血仍然是该治疗的主要安全性问题。假设：已知的基因变异可以改变DOACs药代动力学（PK）中代谢酶或转运蛋白的功能，从而增加出血的风险。目的：评估5个基因（ABCB1、ABCG2、CYP2J2、CYP3A4、CYP3A5）中8个功能激酶相关单核苷酸变异（SNVs）与非瓣膜性房颤DOACs出血风险的关系。方法：对2,364名接受利伐沙班或阿哌沙班治疗的白人非瓣膜性房颤患者进行回顾性队列研究。采用密歇根基因组计划生物银行Illumina Infinium CoreExome v12.1头阵列进行基因分型。主要终点是大出血和临床相关的非大出血的综合。Cox比例风险回归与时变分析在未调整和协变量调整模型中评估了8个pk相关snv与doac出血风险的关系。预先指定的主要分析是协变量调整后的加性遗传模型。由于三个snv属于同一单倍型，因此在初级分析中进行了6次检验，因此p值低于bonferroni校正水平8.33e-3认为具有统计学意义。结果：在初步分析中，所有snv均未达到bonferroni校正的统计学显著性水平（均p < 0.1）。在与其他遗传模型的探索性分析中，ABCB1 (rs4148732) GG基因型倾向于与利伐沙班出血风险相关[HR: 1.391 (95%CI: 1.019-1.900)；P = 0.038]但阿哌沙班组无明显差异（P = 0.487）。结论：在2000多名自我认定的房颤白人门诊患者中，8种功能性pk相关基因变异与利伐沙班或阿哌沙班出血均无显著相关性。
Background: Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy. Hypothesis: Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding. Aim: To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (ABCB1, ABCG2, CYP2J2, CYP3A4, CYP3A5) with the risk of bleeding from DOACs in non-valvular AF patients. Methods: A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thus p-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results: In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all p > 0.1). In exploratory analyses with other genetic models, the ABCB1 (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019–1.900); p = 0.038] but not from apixaban (p = 0.487). Conclusion: Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients.
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影响因子：
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作者：
Kuehl, P;Zhang, J;Schuetz, E
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