VASP磷酸化和基因多态性在非心源性缺血性卒中氯吡格雷抵抗的研究

发布时间：2019-05-05 19:57

【摘要】：目的：研究血管舒张刺激磷蛋白（vasodilator stimulated phosphoprotein，VASP）磷酸化及CYP2C19、CYP3A4基因多态性与非心源性缺血性卒中（non-cardioembolic ischemicstroke，NCIS）患者氯吡格雷抵抗（clopidogrel resistance，CR）的关系。希望从生物学指标和遗传学特性识别CR人群，使基础研究向临床应用转化。 方法:我们总共纳入95例急性发作的NCIS患者，通过流式细胞仪检测VASP磷酸化水平，算出服用氯吡格雷前的基态血小板反应指数（baseline platelet reactivity index，BPRI）及服药治疗后第7天的血小板反应指数（post-treatment platelet reactivity index，PPRI），定义PPRI≥50%为氯吡格雷实验室抵抗（laboratory clopidogrel resistance，LCR）。用Sanger法检测CYP2C19*2（681GA）、CYP2C19*3(636GA)、CYP3A4(IVS10+12GA)及CYP3A4(IVS7+894CT)基因位点基因型。记录患者临床资料并随访半年，将在住院期间出现进展性卒中(National Institute of Health stroke scale (NIHSS)评分增加≥2分)，6个月内复发缺血性卒中或其他缺血性血管事件定义为氯吡格雷临床抵抗（clinical clopidogrelresistance,CCR）。 结果:（1）我们研究中BPRI为：75.16%±14.23%，PPRI为：47.65%±16.75%，LCR发生率为41.05%。基因CYP2C1（9681GA）, CYP2C19(636GA)及CYP3A4(IVS10+12GA)的变异基因型GA/AA的比率分别为：15.79%、38.95%及40.00%，CYP3A4(IVS7+894CT)变异基因型CT/TT比率为33.68%。18（18.95%）例发生CCR。（2）CYP2C19（681GA）(χ2=11.16,P=0.001)和CYP2C19(636GA)(χ2=4.829,P=0.028)变异基因型GA/AA发生LCR可能性明显高于野生基因型GG。CYP2C19(681GA)(Odds ratio （OR）:6.272，95%confidence interval(CI）2.162,18.199,P=0.001)及CYP2C19(636GA)(OR5.625，，95%CI1.439,21.583,P=0.013)基因多态性为LCR的危险因素。（3）存在LCR比非LCR患者发生CCR的可能性明显增高（χ2=6.021,P=0.014）；CYP2C19(681GA)变异基因型GA/AA发生CCR概率显著增高(χ2=10.341,P=0.001)。CYP2C19(681GA)(OR7.814，95%CI1.816,33.618P=0.006)、Essen评分(OR8.351，95%CI1.848,37.745P=0.006)及LCR（OR5.881，95%CI1.373,25.192，P=0.017)为CCR的危险因素。 结论：我们研究表明携带CYP2C19（636GA、681GA）变异基因型患者比携带野生基因型患者更容易发生LCR。我们研究还提示在服用氯吡格雷治疗的NCIS患者LCR及CYP2C19基因多态性对临床结局有显著相关，在临床实践中应对LCR及CYP2C19基因多态性进行检测。
[Abstract]:Aim: to investigate the relationship between vasodilator-stimulated phosphoprotein (vasodilator stimulated phosphoprotein,VASP) phosphorylation and CYP2C19,CYP3A4 gene polymorphism and clopidogrel resistance (clopidogrel resistance,CR) in patients with non-cardiogenic ischemic stroke (non-cardioembolic ischemicstroke,NCIS). Hope to identify the population of CR from biological indicators and genetic characteristics, so as to transform basic research into clinical application. Methods: a total of 95 patients with acute attack of NCIS were enrolled. Flow cytometry was used to measure the phosphorylation level of VASP and calculate the ground state platelet response index (baseline platelet reactivity index,) of clopidogrel before taking clopidogrel. BPRI and platelet response index (post-treatment platelet reactivity index,PPRI) on the 7th day after treatment were defined as clopidogrel laboratory resistance to (laboratory clopidogrel resistance,LCR (PPRI 鈮

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