Genetic variants influenced the risk of bleeding and pharmacodynamics of rivaroxaban in patients with nonvalvular atrial fibrillation: A multicentre prospective cohort study.
Genetic variants influenced the risk of bleeding and pharmacodynamics of rivaroxaban in patients with nonvalvular atrial fibrillation: A multicentre prospective cohort study.
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DOI：
10.1002/ctm2.1263
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发表时间：
2023-05
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
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临床应用中观察到利伐沙班的个体差异。本研究旨在确定与非瓣膜性心房颤动 (NVAF) 患者利伐罗巴班药效学变异性和出血风险相关的遗传变异。从 2017 年 6 月到 2019 年 7 月，该研究招募了 257 名接受利伐沙班治疗的 NVAF 患者。通过测定利伐沙班给药后 3 小时的抗 Xa 因子（抗 FXa）水平作为峰浓度来评估药效学。进行全外显子组测序以检测单核苷酸多态性 (SNP)。这项研究已注册（NCT03161496）。 12 个月内的出血事件与抗 FXa 峰值水平显着相关 (p = .027)。 SUSD3 rs76292544 与 12 个月出血事件相关（比值比 [OR]：4.20，95% 置信区间 [CI]：2.17–8.14，p = 6.43×10−5）。五个 SNP，包括 NCMAP rs4553122 (p = 2.29×10−5)、PRF1 rs885821 (p = 7.02×10−5)、PRKAG2 rs12703159 (p = 7.97×10−5)、PRKAG2 rs13224758 (p = 8.70×10−5) 和POU2F3 rs2298579 (p = 8.24×10−5) 与抗 FXa 峰值水平相关。来自 36 个基因（包括 GOT2 rs14221 和 MMP13 rs640198）的 52 个 SNP 的遗传变异可能与利伐沙班疗效引起的 12 个月出血事件相关。接受利伐沙班治疗的 NVAF 患者的抗 FXa 峰值水平与出血事件风险相关。 SUSD3 rs76292544 暗示与 12 个月出血事件相关，5 个 SNP（NCMAP rs4553122、PRF1 rs885821、PRKAG2 rs12703159、rs13224758 和 POU2F3 rs2298579）暗示与抗 FXa 峰值水平相关。抗 Xa 因子峰值水平与利伐沙班的出血事件相关。 SUSD3 rs76292544 的次要等位基因携带者会增加出血风险。五个 SNP 的遗传变异（包括 NCMAP rs4553122、PRF1 rs885821、PRKAG2 rs12703159、PRKAG2 rs13224758 和 POU2F3 rs2298579）与抗 FXa 峰值水平相关。
Individual variability of rivaroxaban was observed in clinical application. This study aimed to identify genetic variants associated with the variability of pharmacodynamics and bleeding risk of rivaroxbaban in patients with nonvalvular atrial fibrillation (NVAF). From June 2017, and July 2019, this study enrolled 257 patients with NVAF receiving rivaroxaban. Pharmacodynamics was assessed by determining anti‐Factor Xa (anti‐FXa) level 3 h after rivaroxaban administration as peak concentration. Whole‐exome sequencing was performed to detected single nucleotide polymorphisms (SNPs). This study was registered (NCT03161496). The bleeding events within 12 months were significantly related to the peak anti‐FXa level (p = .027). SUSD3 rs76292544 was associated with 12‐month bleeding events (odds ratio [OR]: 4.20, 95% confidence interval [CI]: 2.17–8.14, p = 6.43×10−5). Five SNPs including NCMAP rs4553122 (p = 2.29×10−5), PRF1 rs885821 (p = 7.02×10−5), PRKAG2 rs12703159 (p = 7.97×10−5), PRKAG2 rs13224758 (p = 8.70×10−5), and POU2F3 rs2298579 (p = 8.24×10−5) were associated with peak anti‐FXa level. Genetic variants of 52 SNPs from 36 genes including GOT2 rs14221 and MMP13 rs640198 were potentially related to 12‐month bleeding events caused by rivaroxaban's efficacy. Peak anti‐FXa level was associated with risk of bleeding events in patients with NVAF receiving rivaroxaban. SUSD3 rs76292544 was suggestively associated with 12‐month bleeding events and five SNPs (NCMAP rs4553122, PRF1 rs885821, PRKAG2 rs12703159, rs13224758 and POU2F3 rs2298579) were suggestively associated with peak anti‐FXa level. Peak anti‐Factor Xa level was associated with bleeding events of rivaroxaban. Minor allele carriers of SUSD3 rs76292544 increased bleeding risk. Genetic variants of five SNPs, including NCMAP rs4553122, PRF1 rs885821, PRKAG2 rs12703159, PRKAG2 rs13224758 and POU2F3 rs2298579 were associated with peak anti‐FXa level.
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