CYP2C9*3和CYP4F2 rs2108622基因多态性对中国华法林治疗患者过度抗凝和出血并发症的影响: 一项队列研究

doi:10.5246/jcps.2021.06.037

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (6): 484-494.DOI: 10.5246/jcps.2021.06.037

CYP2C9*3和CYP4F2 rs2108622基因多态性对中国华法林治疗患者过度抗凝和出血并发症的影响: 一项队列研究

吴钰珊¹, 阳丽梅²^,^*(), 黄旭慧², 黄烽¹, 韩涛¹

1. 福建医科大学省立临床医学院/福建省立医院心血管外科, 福建福州 350001
2. 福建医科大学省立临床医学院/福建省立医院药学部, 福建福州 350001

收稿日期:2020-11-09 修回日期:2020-12-24 接受日期:2021-01-16 出版日期:2021-06-29 发布日期:2021-06-29
通讯作者: 阳丽梅
作者简介:
+ Tel.: +86-591-88216353, E-mail: yanglimei_214@163.com
基金资助:
Startup Fund for scientific research, Fujian Medical University (Grant No. 2017XQ010), and Beijing Medical and Health Foundation (Grant No. B183023), China.

Influence of CYP2C9*3 and CYP4F2 rs2108622 gene polymorphisms on over-anticoagulation and bleeding complications of warfarin therapy in Chinese patients: a cohort study

Yushan Wu¹, Limei Yang²^,^*(), Xuhui Huang², Feng Huang¹, Tao Han¹

1 Cardiac surgery, Provincial Clinical College of Fujian Medical University/Fujian Provincial Hospital, Fuzhou 350001, China
2 Pharmacy Department, Provincial Clinical College of Fujian Medical University/Fujian Provincial Hospital, Fuzhou, 350001, China

Received:2020-11-09 Revised:2020-12-24 Accepted:2021-01-16 Online:2021-06-29 Published:2021-06-29
Contact: Limei Yang

摘要/Abstract

摘要：

本研究通过回顾性队列研究, 明确CYP2C9*3和CYP4F2 rs2108622基因多态性对华法林治疗相关的过度抗凝和出血并发症的影响。共纳入196例患者, 其中男性80例, 平均年龄50.8±10.7岁, 平均随访26.9±11.8个月。患者行心脏瓣膜置换术后且服用华法林3个月以上, 目标国际标准化比值(INR)控制在1.8–2.5。采用聚合酶链反应(PCR)-基因测序法检测CYP2C9*3和CYP4F2 rs2108622基因型, 采用SPSS19.0软件分析基因型与华法林相关过度抗凝和出血并发症的关系。在434患者年中, 共发生严重出血18例, 轻度出血59例。与*1/*1携带者相比, CYP2C9*1/*3患者存在更高的过度抗凝风险(HR 7.10; 95% CI: 2.54–19.79, P < 0.001)。CYP4F2 rs2108622突变基因型不显著增加出血(HR 0.89; 95% CI: 0.43–1.82, P = 0.74)或过度抗凝(HR 0.43; 95% CI: 0.16–1.13, P = 0.09)风险。Kaplan-Meier生存曲线显示, CYP2C9 *1/*3携带者过度抗凝时间明显短于*1/*1携带者(log-rank检验, P < 0.001), 而CYP4F2 rs2108622突变基因型患者过度抗凝时间较野生型患者长(P = 0.05)。CYP2C9*3和CYP4F2 rs2108622可能是中国患者华法林治疗中过度抗凝的主要预测因素。

关键词: 抗凝, 遗传学, 出血障碍和凝血障碍, 风险管理

Abstract:

In this retrospective cohort study, we aimed to identify the influence of the CYP2C9*3 and CYP4F2 rs2108622 gene alleles on over-anticoagulation and bleeding complications associated with warfarin therapy. A total of 196 patients were included, including 80 males, the mean age was 50.8±10.7 years, and the average follow-up was 26.9±11.8 months. These patients underwent heart valve replacement surgery in the Cardiovascular Surgery of Fujian Provincial Hospital between January 2018 and August 2019, who took warfarin for at least 3 months and had target international normalized ratio (INR) between 1.8 and 2.5. Genotypes of CYP2C9*3 and CYP4F2 rs2108622 genes were tested by polymerase chain reaction (PCR)-gene sequencing technique. SPSS19.0 software was utilized to analyze the association between genotypes and warfarin-related over-anticoagulation and bleeding complications. Of the 434 patient-years, 18 severe bleedings and 59 mild ones occurred in 31 patients. Patients with CYP2C9 *1/*3 were associated with a higher over-anticoagulation risk compared with the *1/*1 carriers (hazard rate (HR) 7.10; 95% confidence interval (CI): 2.54–19.79, P < 0.001). The CYP4F2 rs2108622 mutant genotype did not cause significant increase in bleeding risk (HR 0.89; 95% CI: 0.43–1.82, P = 0.74) or over-anticoagulation (HR 0.43; 95% CI: 0.16–1.13, P = 0.09). Meanwhile, Kaplan-Meier survival curves showed that the time to over-anticoagulation in CYP2C9 *1/*3 carriers was significantly shorter compared with the *1/*1 carriers (log-rank test, P<0.001), while that in CYP4F2 rs2108622 mutant genotype patients was longer compared with the wild-type patients (P = 0.05). CYP2C9*3 and CYP4F2 rs2108622 might be major predictive factors of over-anticoagulation for warfarin therapy in Chinese patients.

Key words: Anticoagulation, Genetics, Bleeding disorders &, coagulopathies, Risk management

Supporting:

吴钰珊, 阳丽梅, 黄旭慧, 黄烽, 韩涛. CYP2C9*3和CYP4F2 rs2108622基因多态性对中国华法林治疗患者过度抗凝和出血并发症的影响: 一项队列研究[J]. 中国药学(英文版), 2021, 30(6): 484-494.

Yushan Wu, Limei Yang, Xuhui Huang, Feng Huang, Tao Han. Influence of CYP2C9*3 and CYP4F2 rs2108622 gene polymorphisms on over-anticoagulation and bleeding complications of warfarin therapy in Chinese patients: a cohort study[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(6): 484-494.

图/表 6

Table 1. Gene frequency and Hardy-Weinberg equilibrium test.

Table 2. Demographic characteristics and clinical features of patients.

Table 3. The incidence rate of over-anticoagulation and bleeding complications in CYP2C9*3 and CYP4F2 rs2108622 genotypes.

Table 4. HR and 95% CI of the influence of CYP2C9*3 heterozygous mutant on over-anticoagulation and bleeding complications.

Figure 1. Kaplan-Meier curves of CYP2C9*3, CYP4F2 rs2108622 genotypes and over-anticoagulation. (a) CYP2C9*3 genotypes and over-anticoagulation; (b) CYP4F2 rs2108622 genotypes and over-anticoagulation.

Table 5. HR and 95% CI of the influence of CYP4F2 rs2108622 mutant type on over-anticoagulation and bleeding complications.

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CYP2C9*3和CYP4F2 rs2108622基因多态性对中国华法林治疗患者过度抗凝和出血并发症的影响: 一项队列研究

Influence of CYP2C9*3 and CYP4F2 rs2108622 gene polymorphisms on over-anticoagulation and bleeding complications of warfarin therapy in Chinese patients: a cohort study

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