氯吡格雷对冠心病患者PCI术后CYP2C19、PON1基因多态性与FIB、D-二聚体水平的相关性研究
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摘要
目的:分析冠心病患者经皮冠状动脉介入治疗(PCI)术后,规律服用氯吡格雷治疗时CYP2C19、PON1基因多态性与血浆纤维蛋白原(FIB)、D-二聚体水平的相关性研究。方法:选取在某三甲医院确诊为冠心病且行PCI术的患者217例,对217例患者行CYP2C19~*2、CYP2C19~*3、CYP2C19~*17、PON1基因监测,观察患者在规律服用氯吡格雷治疗(75 mg·d~(-1)) 1个月以上的血浆FIB、D-二聚体指标。结果:在217名患者中CYP2C19~*17基因未检测出突变型等位基因,因此对超快代谢型基因不做统计分析。CYP2C19基因的快代谢型、中间代谢型、慢代谢型之间的FIB指标对比均无统计学差异(P> 0. 05);快代谢型与中间代谢型、快代谢性与慢代谢型之间的D-二聚体指标均无统计学差异(P> 0. 05);中间代谢型与慢代谢型之间D-二聚体指标有统计学差异(P <0. 05)。PON1基因GG型与GA型、GG型与AA型、GA型与AA型的FIB和D-二聚体指标水平均无统计学差异(P>0. 05)。结论:携带CYP2C19慢代谢基因型的患者使用常规氯吡格雷剂量治疗,增加血栓风险,可考虑适当增加氯吡格雷服药剂量或改服替格瑞洛进行溶栓治疗。PON1基因多态性与氯吡格雷治疗血小板反应性差异并无关联性。
Objective: Analyze the correlation between CYP2C19,PON1 gene polymorphisms and FIB and D-Dimer levels in patients with coronary heart disease in Yunnan after PCI. Methods: 217 patients diagnosed with coronary heart disease and undergoing PCI in a top three hospital. CYP2 C19~*2,CYP2C19~*3,CYP2C19~*17 and PON1 gene monitoring were performed in all patients. Observe the plasma FIB and D-Dimer indicators of patients who regularly took clopidogrel( 75 mg·d~(-1)) for more than one month. Results: No mutational allele was detected in the CYP2C19~*17 gene in 217 patients,so the ultrafast metabolome group was not statistically analyzed. There was no statistically significant difference in the FIB index between the fast metabolite,intermediate metabolite and slow metabolites of CYP2C19 gene( P > 0. 05). There was no significant difference in D-Dimer between fast metabolite and intermediate metabolite,fast metabolizing and slow metabolizing( P > 0. 05). There was a statistically significant difference between the D-Dimer index between the intermediate metabolite and the slow metabolite( P < 0. 05). There was no significant difference in the PON1 gene GG type and GA type,GG type and AA type,GA type and AA type FIB and D-Dimer index( P > 0. 05). Conclusion: Patients with CYP2 C19 slow-metabolizing genotypes have an increased risk of thrombosis when treated with conventional clopidogrel doses. Should be appropriate to increase the dose of clopidogrel or change to telgrelor for thrombolytic therapy. There was no association between PON1 gene polymorphism and clopidogrel in the treatment of platelet reactivity.
Objective: Analyze the correlation between CYP2C19,PON1 gene polymorphisms and FIB and D-Dimer levels in patients with coronary heart disease in Yunnan after PCI. Methods: 217 patients diagnosed with coronary heart disease and undergoing PCI in a top three hospital. CYP2 C19~*2,CYP2C19~*3,CYP2C19~*17 and PON1 gene monitoring were performed in all patients. Observe the plasma FIB and D-Dimer indicators of patients who regularly took clopidogrel( 75 mg·d~(-1)) for more than one month. Results: No mutational allele was detected in the CYP2C19~*17 gene in 217 patients,so the ultrafast metabolome group was not statistically analyzed. There was no statistically significant difference in the FIB index between the fast metabolite,intermediate metabolite and slow metabolites of CYP2C19 gene( P > 0. 05). There was no significant difference in D-Dimer between fast metabolite and intermediate metabolite,fast metabolizing and slow metabolizing( P > 0. 05). There was a statistically significant difference between the D-Dimer index between the intermediate metabolite and the slow metabolite( P < 0. 05). There was no significant difference in the PON1 gene GG type and GA type,GG type and AA type,GA type and AA type FIB and D-Dimer index( P > 0. 05). Conclusion: Patients with CYP2 C19 slow-metabolizing genotypes have an increased risk of thrombosis when treated with conventional clopidogrel doses. Should be appropriate to increase the dose of clopidogrel or change to telgrelor for thrombolytic therapy. There was no association between PON1 gene polymorphism and clopidogrel in the treatment of platelet reactivity.
引文
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[19] Ma WF,Liang Y,Zhang Y,et al. Relationship of paraoxonase-1 Q192R genotypes and in-stent restenosis and re-stenting in Chinese patients after coronary stenting[J]. Atherosclerosis. 2016,251(4):305-310.
[20] Erathi HV,Durgaprasad R,Velam V,et al. Evaluation of On-Clopidogrel platelet reactivity overtime,SYNTAX SCORE,genetic polymorphisms and their relationship to one year clinical outcomes in STEMI patients undergoing PCI[J]. Minerva Cardioangiol. 2017,10(31):17-25.
[21] ZY Liang,YL Han,XL Zhang,et al. The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up:outcomes in patients with acute coronary syndrome after drug-eluting stent implantation[J].Eurointervention,2013,9(3):316-327.
[2] Nguyen TA,Diodati JG,Pharand C. Resistance to clopidogrel:a review of the evidence[J]. J Am Coll Cardiol,2005,45(8):1157-1164.
[3] Marchini JF,Pinto MR,Novaes GC,et al. Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients[J]. Brazilian Journal of Medical&Biological Research,2017,50(1):e5660.
[4]李世武,陈瑶,张继红,等. PON1基因Q192R多态与氯吡格雷临床疗效及安全关联性的Meta分析(英文)[J].中国新药与临床杂志,2015,34(9):707-720.
[5]黄勤,尹秋林,胡耀. PON1基因Q192R位点多态性与氯吡格雷抵抗的临床研究[J].临床心血管病杂志,2014,30(12):1053-1055.
[6]王伊龙.从东西方种族差异看缺血性卒中抗血小板治疗策略选择[J].中国卒中杂志,2018,13(5):494-499.
[7]李静,郑伶利,陈静,等.基因突变检测在个体化用药中的研究进展[J].现代药物与临床,2018,33(4):1002-1008.
[8]郭松铎,陶月玉,林尚楠.心脏学词典[M].中国医药科技出版社,1998:705.
[9]郝金红,樊英,杨树森.纤维蛋白原、D-二聚体、脂蛋白(a)、外周血白细胞与冠心病的相关研究[J].齐齐哈尔医学院学报,2006,27(12):1409-1411.
[10]梁少兰,靳文,杜作义,等. hs-CRP、BNP及D-二聚体与ACS近期不良心血管事件的关系[J].临床心血管病杂志,2014,30(7):583-585.
[11]夏磊,杨文,李斌,陈思锦.非ST段抬高急性冠状动脉综合征患者血浆D-二聚体与GRACE评分的相关研究[J].临床心血管病杂志,2015,31(8):847-850.
[12] El-Sherbeni AA,El-Kadi AO. Repurposing Resveratrol and Fluconazole To Modulate Human Cytochrome P450-Mediated Arachidonic Acid Metabolism[J]. Mol Pharm,2016,13(4):1278-1288.
[13]樊丹君,陈进,李晨怡,等. CYP2C19基因多态性与心血管疾病的研究进展[J].心脑血管病防治,2018,18(3):230-235.
[14] Akasaka T,Sueta D,Arima Y,et al. CYP2C19 variants and epoxyeicosatrienoic acids in patients with microvascular angina[J]. IJC Heart&Vasculature,2017,12(15):15-20.
[15]吴曾繁,吴剑胜,胡雪松,等. PON1基因多态性和冠心病关系的研究进展[J].医学综述,2010,16(3):321-324.
[16] MuchováJ,AndrezálováL,Oravec S,et al. High density lipoprotein subfractions and paraoxonase 1 in children[J]. Acta Biochim Pol,2016,63(3):555-563.
[17] Tao Liu,Tao Yin,Yan Li,et al. CYP2C19 polymorphisms and coronary heart disease risk factors synergistically impact clopidogrel response variety after percutaneous coronary intervention[J]. Coronary Artery Disease,2014,25(5):593-597.
[18] Pan Y,Chen W,Xu Y,et al. Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack:A Systematic Review and Meta-Analysis[J]. Circulation,2017,135(1):21-33.
[19] Ma WF,Liang Y,Zhang Y,et al. Relationship of paraoxonase-1 Q192R genotypes and in-stent restenosis and re-stenting in Chinese patients after coronary stenting[J]. Atherosclerosis. 2016,251(4):305-310.
[20] Erathi HV,Durgaprasad R,Velam V,et al. Evaluation of On-Clopidogrel platelet reactivity overtime,SYNTAX SCORE,genetic polymorphisms and their relationship to one year clinical outcomes in STEMI patients undergoing PCI[J]. Minerva Cardioangiol. 2017,10(31):17-25.
[21] ZY Liang,YL Han,XL Zhang,et al. The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up:outcomes in patients with acute coronary syndrome after drug-eluting stent implantation[J].Eurointervention,2013,9(3):316-327.