Yee Jeong, Song Tae-Jin, Yoon Ha-Young, Park Junbeom, Gwak Hye-Sun
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
Department of Neurology, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul 07804, Korea.
Pharmaceutics. 2022 Jan 19;14(2):231. doi: 10.3390/pharmaceutics14020231.
The purpose of this study was to identify the renin-angiotensin system (RAS)-related genetic factors associated with bleeding and develop the bleeding risk scoring system in patients receiving direct oral anticoagulants (DOACs). This study was a retrospective analysis of prospectively collected samples from June 2018 to May 2020. To investigate the associations between RAS-related genetic factors and major bleeding, we selected 16 single nucleotide polymorphisms (SNPs) from five genes (namely, , , , , and ). Multivariable logistic regression analysis was employed to investigate the independent risk factors for bleeding and to develop a risk scoring system. A total of 172 patients were included in the analysis, including 33 major bleeding cases. Both old age (≥65 years) and moderate to severe renal impairment (CrCl < 50 mL/min) increased the risk of bleeding in the multivariable analysis. Among RAS-related polymorphisms, patients carrying TT genotype of rs5050 and A allele of rs4353 experienced a 3.6-fold (95% CI: 1.4-9.3) and 3.1-fold (95% CI: 1.1-9.3) increase in bleeding, respectively. The bleeding risk increased exponentially with a higher score; the risks were 0%, 2.8%, 16.9%, 32.7%, and 75% in patients with 0, 1, 2, 3, and 4 points, respectively. Although this study is limited to a retrospective study design, this is the first study to suggest RAS-related genetic markers and risk scoring systems, including both clinical and genetic factors, for major bleeding in patients receiving DOAC treatment.
本研究的目的是确定与出血相关的肾素 - 血管紧张素系统（RAS）相关遗传因素，并开发接受直接口服抗凝剂（DOACs）治疗患者的出血风险评分系统。本研究是对2018年6月至2020年5月前瞻性收集样本的回顾性分析。为了研究RAS相关遗传因素与大出血之间的关联，我们从五个基因（即 ， ， ， ，和 ）中选择了16个单核苷酸多态性（SNP）。采用多变量逻辑回归分析来研究出血的独立危险因素并开发风险评分系统。共有172例患者纳入分析，其中包括33例大出血病例。在多变量分析中，老年（≥65岁）和中度至重度肾功能损害（肌酐清除率<50 mL/分钟）均增加了出血风险。在RAS相关多态性中，携带rs5050的TT基因型和rs4353的A等位基因的患者出血风险分别增加了3.6倍（95%CI：1.4 - 9.3）和3.1倍（95%CI：1.1 - 9.3）。出血风险随着得分升高呈指数增加；得0分、1分、2分、3分和4分的患者出血风险分别为0%、2.8%、16.9%、32.7%和75%。尽管本研究限于回顾性研究设计，但这是第一项提出RAS相关遗传标记和风险评分系统的研究，该系统包括临床和遗传因素，用于接受DOAC治疗患者的大出血情况。
