【摘要】：目的：研究血管舒張刺激磷蛋白（vasodilator stimulated phosphoprotein，VASP）磷酸化及CYP2C19、CYP3A4基因多態(tài)性與非心源性缺血性卒中（non-cardioembolic ischemicstroke，NCIS）患者氯吡格雷抵抗（clopidogrel resistance，CR）的關(guān)系。希望從生物學(xué)指標(biāo)和遺傳學(xué)特性識別CR人群，使基礎(chǔ)研究向臨床應(yīng)用轉(zhuǎn)化。 方法:我們總共納入95例急性發(fā)作的NCIS患者，通過流式細(xì)胞儀檢測VASP磷酸化水平，算出服用氯吡格雷前的基態(tài)血小板反應(yīng)指數(shù)（baseline platelet reactivity index，BPRI）及服藥治療后第7天的血小板反應(yīng)指數(shù)（post-treatment platelet reactivity index，PPRI），定義PPRI≥50%為氯吡格雷實驗室抵抗（laboratory clopidogrel resistance，LCR）。用Sanger法檢測CYP2C19*2（681GA）、CYP2C19*3(636GA)、CYP3A4(IVS10+12GA)及CYP3A4(IVS7+894CT)基因位點基因型。記錄患者臨床資料并隨訪半年，將在住院期間出現(xiàn)進(jìn)展性卒中(National Institute of Health stroke scale (NIHSS)評分增加≥2分)，6個月內(nèi)復(fù)發(fā)缺血性卒中或其他缺血性血管事件定義為氯吡格雷臨床抵抗（clinical clopidogrelresistance,CCR）。 結(jié)果:（1）我們研究中BPRI為：75.16%±14.23%，PPRI為：47.65%±16.75%，LCR發(fā)生率為41.05%。基因CYP2C1（9681GA）, CYP2C19(636GA)及CYP3A4(IVS10+12GA)的變異基因型GA/AA的比率分別為：15.79%、38.95%及40.00%，CYP3A4(IVS7+894CT)變異基因型CT/TT比率為33.68%。18（18.95%）例發(fā)生CCR。（2）CYP2C19（681GA）(χ2=11.16,P=0.001)和CYP2C19(636GA)(χ2=4.829,P=0.028)變異基因型GA/AA發(fā)生LCR可能性明顯高于野生基因型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)基因多態(tài)性為LCR的危險因素。（3）存在LCR比非LCR患者發(fā)生CCR的可能性明顯增高（χ2=6.021,P=0.014）；CYP2C19(681GA)變異基因型GA/AA發(fā)生CCR概率顯著增高(χ2=10.341,P=0.001)。CYP2C19(681GA)(OR7.814，95%CI1.816,33.618P=0.006)、Essen評分(OR8.351，95%CI1.848,37.745P=0.006)及LCR（OR5.881，95%CI1.373,25.192，P=0.017)為CCR的危險因素。 結(jié)論：我們研究表明攜帶CYP2C19（636GA、681GA）變異基因型患者比攜帶野生基因型患者更容易發(fā)生LCR。我們研究還提示在服用氯吡格雷治療的NCIS患者LCR及CYP2C19基因多態(tài)性對臨床結(jié)局有顯著相關(guān)，在臨床實踐中應(yīng)對LCR及CYP2C19基因多態(tài)性進(jìn)行檢測。
[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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