目的：基药物基因组学研究显示，基因多态性对直接口服抗凝药（DOACs）的血药浓度变异具有决定性影响。本研究旨在系统探讨关键基因突变对中国非瓣膜性心房颤动（NVAF）患者DOACs治疗临床结局的影响，为制定个体化抗凝方案提供循证依据。

方法：本研究采用单中心、回顾性队列设计，纳入2022年9月至2023年12月期间接受达比加群酯、利伐沙班或艾多沙班治疗的720例NVAF患者。通过多重PCR结合二代测序技术，对ABCB1、CES1等7个关键药物代谢转运基因的9个SNP位点进行基因分型。采用Cox比例风险回归模型，比较不同基因型患者的出血和血栓栓塞事件发生率，并校正年龄、性别等混杂因素。

结果：在达比加群治疗组，携带CES1 rs2244613 C等位基因的患者表现出明显的出血风险降低，其调整后风险比（aHR）为0.33（95%CI：0.13-0.85，P=0.021），相当于绝对风险降低达66.7%。利伐沙班治疗组的数据显示，ABCB1 rs1045642 T等位基因携带者的血栓栓塞风险显著降低81%（aHR=0.19，95%CI：0.07-0.57，P=0.003）。此外，在艾多沙班治疗组中观察到SLCO1B1 rs4149056 C等位基因与出血风险之间存在临界统计学意义的相关性（P=0.052），虽然未达到传统显著性阈值，但这一趋势仍具有潜在的临床参考价值。

结论：本研究发现CES1 rs2244613和ABCB1 rs1045642基因多态性分别与达比加群和利伐沙班的治疗效果显著相关。这些遗传标记可作为预测中国NVAF患者DOACs治疗结局的重要生物标志物，为实施精准抗凝治疗提供新思路。建议临床对CES1 rs2244613 AA基因型患者加强出血监测，对ABCB1 rs1045642 T等位基因携带者优化血栓预防策略。未来需开展前瞻性研究验证这些发现，并建立中国人群特异的DOACs药物基因组学指导方案。

Background: Gene polymorphisms play a critical role in the variability of plasma concentrations of direct-acting oral anticoagulants (DOACs). In this study, we aimed to investigate the effects of genetic variants on the clinical outcomes of Chinese patients treated with DOACs.

Methods: The retrospective study recruited 720 patients with nonvalvular atrial fibrillation who were receiving dabigatran, rivaroxaban, or edoxaban. Cox regression models were employed to compare the clinical outcomes between carriers and non-carriers of the key single nucleotide polymorphisms.

Results: Results revealed that the CES1 rs2244613 C allele significantly reduced bleeding events in patients treated with dabigatran (adjusted hazard ratio [aHR] 0.33, 95% confidence interval [CI], 0.13–0.85, P = 0.021). The carriage of ABCB1 rs1045642 T allele was associated with a lower risk of thromboembolism in rivaroxaban users (aHR 0.19, 95% CI 0.07–0.57, P = 0.003).Additionally, a trend toward statistical significance (P = 0.052) was observed between the SLCO1B1 rs4149056 C allele and bleeding risk among the edoxaban users.

Conclusions: Our study showed that the CES1 rs2244613 and ABCB1 rs1045642 alleles were associated with outcome events in Chinese patients taking dabigatran and rivaroxaban,respectively.The findings could help predict clinical outcomes and develop personalized anticoagulation treatment strategies for Chinese patients taking DOACs.