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中华普通外科学文献(电子版)

中华普通外科学文献(电子版) ›› 2015, Vol. 09 ›› Issue (01) : 13 -17. doi: 10.3877/cma.j.issn.1674-0793.2015.01.004

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论著

CYP2C19基因多态性与下肢动脉硬化闭塞症腔内治疗术后再缺血的相关性研究
郭宝磊1(), 符伟国1, 郭大乔1,†(), 史振宇1, 王利新1, 唐骁1, 李炜淼1   
  1. 1. 200032　上海，复旦大学附属中山医院血管外科
  • 收稿日期:2014-11-25 出版日期:2015-02-01
  • 通信作者: 郭宝磊, 郭大乔

Association of CYP2C19 genotype and platelet responsiveness with clinical efficacy of clopidogrel therapy in patients with arteriosclerosis obliterans after stent implantation

Baolei Guo1,†(), Weiguo Fu1, Daqiao Guo1(), Zhenyu Shi1, Lixin Wang1, Xiao Tang1, Weimiao Li1   

  1. 1. Department of Vascular Surgery, Zhong-shan Hospital, Fudan University, Shanghai 200032, China
  • Received:2014-11-25 Published:2015-02-01
  • Corresponding author: Baolei Guo, Daqiao Guo
  • About author:
    Corresponding author: Guo Daqiao, Email:
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郭宝磊, 符伟国, 郭大乔, 史振宇, 王利新, 唐骁, 李炜淼. CYP2C19基因多态性与下肢动脉硬化闭塞症腔内治疗术后再缺血的相关性研究[J]. 中华普通外科学文献(电子版), 2015, 09(01): 13-17.

Baolei Guo, Weiguo Fu, Daqiao Guo, Zhenyu Shi, Lixin Wang, Xiao Tang, Weimiao Li. Association of CYP2C19 genotype and platelet responsiveness with clinical efficacy of clopidogrel therapy in patients with arteriosclerosis obliterans after stent implantation[J]. Chinese Archives of General Surgery(Electronic Edition), 2015, 09(01): 13-17.

目的

探讨调控氯吡格雷代谢活性相关基因CYP2C19的单核苷酸多态性与下肢动脉硬化闭塞症(ASO)腔内治疗术后再狭窄的相关性。

方法

2011年1月至2012年7月共纳入单纯行股浅动脉腔内支架植入术的ASO患者(TASCⅡA-C)74例。患者服用氯吡格雷(75 mg/d)和阿司匹林肠溶片(100 mg/d)双联抗血小板治疗5 d后,通过实时定量PCR技术检测CYP2C19基因多态性;按照是否携带CYP2C19等位基因缺失型分为LOF携带组和LOF非携带组,同时行血栓弹力图检测血小板反应性。术后1、3、6和12个月分别评估支架的通畅程度。

结果

50例(67.6%)患者完成12个月随访,平均随访时间为(9.8 ± 2.1)个月(1 ~ 30个月)。携带组患者与经二磷酸腺苷(ADP)途径的血小板反应性降低相关(P = 0.022)。携带1个或2个CYP2C19等位基因缺失型[CYP2C19*2和(或)CYP2C19*3]患者可增加下肢再缺血事件的发生(P = 0.008、0.002)。两组患者12个月支架总通畅率为56.0%,LOF携带组和LOF非携带组分别为34.6%和73.1%(P = 0.006)。ADP途径血小板反应性与再缺血事件具有相关性(P = 0.012)。

结论

CYP2C19基因多态性和ADP途径血小板反应性密切相关。CYP2C19等位基因缺失型是预测ASO腔内治疗后再缺血事件的危险因素。

关键词: CYP2C19基因, 下肢动脉硬化性闭塞, 氯吡格雷, 血小板反应性
Objective

To evaluate the relationship between the CYP2C19 genotype and the antiplatelet effect of clopidogrel therapy and to predict the risk of mid-term ischemic events after endovascular treatment of arteriosclerosis obliterans (ASO).

Methods

From January 2011 to July 2012, a total of seventy-four consecutive patients with ASO (TASCⅡA-C) in the superficial femoral artery (SFA) were included in a prospectively maintained database. Patients received a recommended dosage of 75 mg clopidogrel and 100 mg aspirin daily for at least 5 days prior to CYP2C19 single nucleotide polymorphisms TaqMan analysis and the thromboelastography assay of clopidogrel response, before endovascular procedure. Patients were divided into two groups according to CYP 2C19 genotypes. During the follow up, stent patency was assessed at 1-, 3-, 6-, and 12-month postoperatively.

Results

Fifty enrolled patients (67.6%) in the study were completely investigated in follow-up analysis. The mean duration of follow-up was (9.8 ± 2.1) months (range 1-30 months). CYP2C19 loss-of-function (LOF) allele group had a diminished pharmacodynamics response to clopidogrel (P = 0.022). One LOF carriers or two LOF had an increased incidence of ischemic events (P = 0.008, 0.002, respectively). Cumulative primary patency rate at 12 months was 56.0%, with significant differences between the two groups (73.1% vs 34.6%, P = 0.006). According to the ADP-induced platelet aggregation, patients with high platelet reactivity had a significantly higher rate of ischemic events between the two groups (P = 0.012).

Conclusions

CYP2C19 LOF alleles are associated with diminished platelet responses to clopidogrel treatments. The patients who received clopidogrel and with CYP2C19 LOF alleles may trend towards a poor prognosis after endovascular procedures.

Key words: CYP2C19 genotype, Arterosclerosis obliterans, Clopidorel, Platelet reactivity
表1 两组患者基本情况与合并疾病
项目 LOF非携带组 LOF携带组 统计值 P值
例数 24 26 ? ?
年龄(岁) 73 ± 10 74 ± 10 0.312 0.722a
BMI ( ± s,kg/m2) 23.0 ± 2.4 23.1 ± 2.9 0.419 0.865a
性别，男[例(%)] 19(79.2) 20(76.9) 0.037 0.848
糖尿病[例(%)] 11(85.2) 10(38.5) 0.278 0.598
吸烟[例(%)] 4(16.7) 9(34.6) 2.090 0.148
高血压[例(%)] 23(95.8) 20(76.9) 2.302 0.129
CVD[例(%)] 4(16.7) 1(3.8) 1.077 0.299
CAD[例(%)] 6(25.0) 5(19.2) 0.242 0.623
PPIs[例(%)] 1(4.2) 2(7.7) 0.000 1.000
表2 两组患者病变分级、特性和操作细节[例(%), χ2检验]
例数 LOF非携带组 LOF携带组 χ 2值 P值
24 26
Fontaine分级 ? ? 0.855 0.652
? 2 16(66.7) 14(53.8) ? ?
? 3 6(25.0) 9(34.6) ? ?
? 4 2(8.3) 3(11.5) ? ?
病变特性 ? ? 2.580 0.108
? 狭窄 7(29.2) 2(7.7) ? ?
? 闭塞 17(70.8) 24(92.3) ? ?
术后流出道数量 ? ? 0.345 0.842
? 1 6(25.0) 6(23.1) ? ?
? 2 12(50.0) 15(57.7) ? ?
? 3 6(25.0) 5(19.2) ? ?
支架数量 ? ? 1.009 0.604
? 1 12(50.0) 11(42.3) ? ?
? 2 11(45.8) 12(46.2) ? ?
? 3 1(4.2) 3(11.5) ? ?
病变处理位置 ? ? 3.195 0.362
? 单纯SFA 10(41.7) 16(61.5) ? ?
? SFA + POP 3(12.5) 4(15.4) ? ?
? SFA + Tibial 7(29.2) 3(11.5) ? ?
? SFA + POP + Tibial 4(16.7) 3(11.5) ? ?
图1 CYP2C19基因型与ADP途径血小板反应性的相关性
表3 两组患者随访事件(例,χ2检验)
项目 LOF非携带组 LOF携带组 χ2值 P值
例数 24 26 ? ?
死亡 1 2 0.275 0.600
缺血事件 4 15 8.916 0.004
? 症状 ? ? ? ?
? ? 无症状 1 3 ? ?
? ? 再发间跛 2 9 ? ?
? ? 静息痛 1 3 ? ?
? 病变特性 ? ? ? ?
? ? 支架内再狭窄 3 11 ? ?
? ? 闭塞 1 4 ? ?
再次干预事件 3 3 0.011 0.917
? 球囊扩张 2 3 ? ?
? 支架内支架 1 0 ? ?
原药物方案并随访 20 12 7.488 0.008
改变治疗方案 0 9 ? ?
图2 LOF携带组和LOF非携带组Kaplan-Meier生存曲线
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