CYP2C19基因多态性与ADP诱导的RPA相关关系及两者对CHD患者预后的影响
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摘要
目的探究CYP2C19基因多态性与ADP诱导的血小板残余活性(RPA)之间的相关关系,以及两者对冠心病(CHD)患者预后的影响。方法回顾性选取于2014年3月至2016年5月就诊渭南市中心医院的204例CHD患者,其中服用氯吡格雷(75 mg/d维持)的稳定性心绞痛(SA)患者100例,服用阿司匹林(100 mg/d)和氯吡格雷(75 mg/d维持)的ACS患者104例。采用全血电阻法检测体内药物浓度稳定后的RPA,加入ADP或花生四烯酸(AA)作为诱导剂。采用CYP2C19基因检测试剂盒-DNA微阵列芯片法检测受试者的CYP2C19基因多态性。平均随访12个月,记录预后情况,根据预后将观察对象分为发生缺血事件组和未发生缺血事件组。根据CYP2C19基因多态性检测结果,分为高代谢组(EM,CYP2C19*1/*1)、中代谢组(IM,CYP2C19*1/*2或*1/*3)和低代谢组(PM,CYP2C19*2/*2,*2/*3或*3/*3)三组。绘制抗血小板治疗药物低反应RPA界值预测CHD患者预后的ROC曲线,对ADP诱导的RPA及CYP2C19基因多态性与的关系采用Kaplan-Meier生存分析。结果 ADP诱导的RPA在EM、IM、PM组间的差异具有显著性(P <0. 05);而AA诱导的RPA在三组间差异无显著差异(P> 0. 05)。发生缺血事件组RPA水平高于未发生缺血事件组,RPA水平与缺血事件发生显著相关(P <0. 05)。ROC分析示ADP诱导的RPA最佳界值为7. 58Ω,对主要缺血事件的特异度是92. 8%,敏感度是69. 6%;以AA诱导的RPA最佳界值为5. 96Ω,对主要缺血事件的特异度99. 4是%,敏感度是82. 6%。生存分析提示,氯吡格雷低反应性对不良事件的发生有显著影响(P <0. 05),而是否为IM或PM及阿司匹林低反应性对缺血性事件发生的影响无统计学意义(P> 0. 05)。结论 CYP2C19基因多态性可影响ADP诱导的RPA的水平,但其对CHD患者缺血事件的发生无显著影响。而ADP诱导的RPA水平与CHD患者缺血事件的发生显著相关。
Objective To investigate the relationship between CYP2 C19 gene polymorphism and RPA( residual platelet aggregation rate)induced by ADP,and their effects on the prognosis of CHD( coronary heart disease) patients. Methods 204 patients with CHD treated from March 2014 to May 2016 in our hospital were selected. 100 patients with SA were treated with clopidogrel( 75 mg/d maintenance),104 patients with ACS were treated with aspirin( 100 mg/d) and clopidogrel( 75 mg/d maintenance). The whole blood resistance method was used to detect the RPA in vivo when the concentration of drugs were stable,add ADP or arachidonic acid( AA) as an inducer. The CYP2 C19 gene polymorphism of the subjects was detected by CYP2 C19 gene detection kit-DNAmicro array method. The average follow-up period was 12 months. The prognosis was recorded. According to prognosis,the subjects were divided into ischemic event group and non-ischemic event group. The ROC curve was used to evaluate the prognostic value of CHD patients. Kaplan-Meier survival analysis was used to analyze the relationship between ADP induced polymorphism of CYP2 C19 gene and RPA. Results There was no significant difference between the two groups in age,sex,BMI,number of smokers,platelet count before treatment,basic diseases and drug use( P > 0. 05). The difference of ADP induced RPA between EM( CYP2 C19* 1/* 1),IM( CYP2 C19* 1/* 2 or * 1/* 3) and PM( CYP2 C19* 2/* 2,* 2/* 3 or * 3/* 3) group was statistically significant( P < 0. 05),but there was no significant difference between RPA induced by AA of the two groups( P > 0. 05). The level of RPA in the ischemic event group was higher than that in the non-ischemic event group,and the RPA level was significantly correlated with the ischemic event,and the difference was statistically significant( P < 0. 05). The best predict value of RPA induced by ADP was 7. 58 Ω,specificity was92. 8%,sensitivity was 69. 6%; RPA value induced by AA was 5. 96 Ω,the specificity was 99. 4%,sensitivity was 82. 6%. Survival analysis indicated that the low reactivity of clopidogrel was significantly correlated with adverse events( P < 0. 05),and whether the effects of IM or PM and aspirin low reactivity on ischemic events were not statistically significant( P > 0. 05). Conclusion The CYP2 C19 gene polymorphism can affect the level of RPA induced by ADP,but it had no significant effect on the occurrence of ischemic events in CHD patients. The level of RPA induced by ADP was significantly related to the occurrence of ischemic events in CHD patients.
Objective To investigate the relationship between CYP2 C19 gene polymorphism and RPA( residual platelet aggregation rate)induced by ADP,and their effects on the prognosis of CHD( coronary heart disease) patients. Methods 204 patients with CHD treated from March 2014 to May 2016 in our hospital were selected. 100 patients with SA were treated with clopidogrel( 75 mg/d maintenance),104 patients with ACS were treated with aspirin( 100 mg/d) and clopidogrel( 75 mg/d maintenance). The whole blood resistance method was used to detect the RPA in vivo when the concentration of drugs were stable,add ADP or arachidonic acid( AA) as an inducer. The CYP2 C19 gene polymorphism of the subjects was detected by CYP2 C19 gene detection kit-DNAmicro array method. The average follow-up period was 12 months. The prognosis was recorded. According to prognosis,the subjects were divided into ischemic event group and non-ischemic event group. The ROC curve was used to evaluate the prognostic value of CHD patients. Kaplan-Meier survival analysis was used to analyze the relationship between ADP induced polymorphism of CYP2 C19 gene and RPA. Results There was no significant difference between the two groups in age,sex,BMI,number of smokers,platelet count before treatment,basic diseases and drug use( P > 0. 05). The difference of ADP induced RPA between EM( CYP2 C19* 1/* 1),IM( CYP2 C19* 1/* 2 or * 1/* 3) and PM( CYP2 C19* 2/* 2,* 2/* 3 or * 3/* 3) group was statistically significant( P < 0. 05),but there was no significant difference between RPA induced by AA of the two groups( P > 0. 05). The level of RPA in the ischemic event group was higher than that in the non-ischemic event group,and the RPA level was significantly correlated with the ischemic event,and the difference was statistically significant( P < 0. 05). The best predict value of RPA induced by ADP was 7. 58 Ω,specificity was92. 8%,sensitivity was 69. 6%; RPA value induced by AA was 5. 96 Ω,the specificity was 99. 4%,sensitivity was 82. 6%. Survival analysis indicated that the low reactivity of clopidogrel was significantly correlated with adverse events( P < 0. 05),and whether the effects of IM or PM and aspirin low reactivity on ischemic events were not statistically significant( P > 0. 05). Conclusion The CYP2 C19 gene polymorphism can affect the level of RPA induced by ADP,but it had no significant effect on the occurrence of ischemic events in CHD patients. The level of RPA induced by ADP was significantly related to the occurrence of ischemic events in CHD patients.
引文
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[10]Singh M,Williams BA,Gersh BJ,et al.Geographical differences in the rates of angiographic restenosis and ischemia-driven target vessel revascularization after percutaneous coronary interventions:results from the Prevention of Restenosis With Tranilast and its Outcomes(PRES-TO)Trial[J].J Am Coll Cardiol,2006,47(1):34-39.
[11]Oestreich JH,Best LG,Dobesh PP.Prevalence of CYP2C19 variant alleles and pharmacodynamic variability of aspirin and clopidogrel in Native Americans[J].Am Heart J,2014,167(3):413-418.
[12]Bhatt DL,ParéG,Eikelboom JW,et al.The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients:the CHARISMA genetics study[J].Eur Heart J,2012,33(17):2143-2150.
[13]Shuldiner AR,O'Connell JR,Bliden KP,et al.Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy[J].JAMA,2009,302(8):849.
[14]Herter JM,Rossaint J,Zarbock A.Platelets in inflammation and immunity[J].J Thromb Haemost,2014,12(11):1764-1775.
[15]Sedky HA,El-Sewefy DA,Saad AA,et al.Clinical significance of baseline platelet reactivity in patients with acute coronary syndrome[J].Clin Appl Thromb Hemost,2013,19(3):256-260.
[2]Angiolillo DJ,Fernández-Ortiz A,Bernardo E,et al.High clopidogrel loading dose during coronary stenting:effects on drug response and interindividual variability[J].Eur Heart J,2004,25(21):1903-1910.
[3]Weeke P,Roden DM.Applied pharmacogenomics in cardiovascular medicine[J].Annu Rev Med,2014,65(81-94.
[4]Marcucci R,Gori AM,Paniccia R,et al.Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay:a 12-month follow-up[J].Circulation,2009,119(2):237-242.
[5]Hochholzer W,Trenk D,Fromm MF,et al.Impact of cytochrome P4502C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement[J].J Am Coll Cardiol,2010,55(22):2427-2434.
[6]Mrginean A,Bnescu C,Moldovan V,et al.The Impact of CYP2C19Loss-of-Function Polymorphisms,Clinical,and Demographic Variables on Platelet Response to Clopidogrel Evaluated Using Impedance Aggregometry[J].Clin Appl Thromb Hemost,2017,23(3):255-265.
[7]Sun H,Qu Q,Chen ZF,et al.Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention[J].Front Pharmacol,2016,7:453.
[8]Doll JA,Neely ML,Roe MT,et al.Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel[J].J Am Coll Cardiol,2016,67(8):936-947.
[9]吴丹,杨胜利,路靖,等冠心病患者支架术后根据检测药物代谢酶CYP2C19基因调整抗血小板治疗的价值[J].中国循环杂志,2015,30(3):216-219.
[10]Singh M,Williams BA,Gersh BJ,et al.Geographical differences in the rates of angiographic restenosis and ischemia-driven target vessel revascularization after percutaneous coronary interventions:results from the Prevention of Restenosis With Tranilast and its Outcomes(PRES-TO)Trial[J].J Am Coll Cardiol,2006,47(1):34-39.
[11]Oestreich JH,Best LG,Dobesh PP.Prevalence of CYP2C19 variant alleles and pharmacodynamic variability of aspirin and clopidogrel in Native Americans[J].Am Heart J,2014,167(3):413-418.
[12]Bhatt DL,ParéG,Eikelboom JW,et al.The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients:the CHARISMA genetics study[J].Eur Heart J,2012,33(17):2143-2150.
[13]Shuldiner AR,O'Connell JR,Bliden KP,et al.Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy[J].JAMA,2009,302(8):849.
[14]Herter JM,Rossaint J,Zarbock A.Platelets in inflammation and immunity[J].J Thromb Haemost,2014,12(11):1764-1775.
[15]Sedky HA,El-Sewefy DA,Saad AA,et al.Clinical significance of baseline platelet reactivity in patients with acute coronary syndrome[J].Clin Appl Thromb Hemost,2013,19(3):256-260.