CYP2C19基因多态性与缺血性脑血管病患者PTAS术后氯吡格雷反应性的关联研究

Correlation study of gene polymorphism of CYP2C19 and clopidogrel response after percutaneous transluminal angioplasty and stenting in patients with ischemic cerebrovascular disease

目的关于CYP2C19基因多态性与缺血性脑血管病患者经皮血管内支架成形术（percutaneous transluminal angioplasty and stenting,PTAS）术后氯吡格雷反应性的研究较少。文中旨在探讨缺血性脑血管病患者在PTAS及规律服用双联抗血小板治疗6个月后,CYP2C19基因多态性与氯吡格雷治疗后血小板高反应性（high on-treatment platelet reactivity,HTPR）的关系及其对PTAS术后支架内再狭窄（in-stent restenosis,ISR）的影响。方法连续性纳入南京军区南京总医院神经内科2011年1月至2014年3月期间行PTAS治疗的缺血性脑血管病患者145例,根据基因测序结果将患者分为野生型组（CYP219＊1/＊1,69例）和突变组（杂合突变型CYP2C19＊1/＊2与纯合突变型CYP2C19＊2/＊2,76例）。术后予阿司匹林100 mg/d、氯吡格雷75 mg/d维持剂量治疗。通过TEG软件测定血小板二磷酸腺苷（adenosine diphosphate,ADP）受体抑制率;通过血栓弹力图测定PTAS术后6个月的HTPR;常规行脑动脉数字减影血管造影评估血管支架内有无再狭窄,并通过Logistic回归分析患者PTAS术后及氯吡格雷治疗后HTPR的影响因素。结果突变组ADP受体抑制率[（45.22±22.96）%]较野生型组[（58.43±21.98）%]明显减弱（P=0.001）。突变组中杂合突变型为（47.80±22.93）%,纯合突变型为（37.53±21.84）%。突变组HTPR发生率高于野生型组（35.5%vs 17.4%,P=0.014）。多因素Logistic回归分析显示CYP2C19＊2基因为PTAS术后及氯吡格雷治疗后HTPR的独立危险因素（OR=2.356,CI：1.053～5.272）,CYP2C19＊2基因携带者ISR发生率高于野生型患者（11.8%vs 1.4%,P=0.019）。结论 CYP2C19＊2位点多态性可能是缺血性脑血管病患者PTAS术后发生HTPR的重要影响因素,与ISR的形成相关。

Objective There is little research on the relationship of gene polymorphism of CYP2C19 and clopidogrel response after percutaneous transluminal angioplasty and stenting（ PTAS） in patients with ischemic cerebrovascular disease. The study aimed to investigate the relationship between gene polymorphism and high on-treatment platelet reactivity（ HTPR） after PTAS and 6months of regular dual antiplatelet administration in patients. Methods A total of 145 Chinese patients treated with PTAS in our department from January 2011 to March 2014 were enrolled in this study. According to the gene sequencing,patients were divided into wild-type group（ CYP2C19＊ 1/＊ 1,69 cases） and mutation group（ heterozygous mutation CYP2C19＊ 1/＊ 2 and homozygous mutation CYP2C19＊ 2/＊ 2,76 cases）. Patients received a 100 mg/d aspirin and 75 mg/d clopidogrel maintenance dose（ MD） as dual antiplatelet therapy after PTAS. The clopidogrel inhibition effect was measured by thrombelastography（ TEG） system 6 months after PTAS.Routine cerebral artery digital subtraction angiography was applied to evaluate whether there was restenosis in stent and logistic regression analysis was used to analyze the influential factors of HTPR after PTAS and clopidogrel adminstration. Results After 6 months＇ regular administration of clopidogrel after PTAS,the platelet adenosine diphosphate（ ADP） receptor inhibition rates in wild-type group,heterozygous mutation and homozygous mutation group were respectively（ 58. 43 ± 21. 98） %,（ 47. 80 ± 22. 93） %,（ 37. 53 ±21. 84） %. The platelet ADP receptor inhibition rate was significantly decreased compared with wild-type group（ P = 0. 001）. Carriers of at least one CYP2C19 loss-of-function（ LOF） allele had a higher frequency of clopidogrel HTPR（ 35. 5% vs17. 4 % for patients with and without LOF alleles,respectively; P = 0. 014）. Using multivariate logistic regression analysis,the carriage of CYP2C19 LOF alleles was an independent predictor of the post-procedure HTPR（ OR = 2. 356,95% CI： 1. 053- 5. 272,P = 0. 037）. The rate of ISR was remarkably higher in patients with at least one CYP2C19＊ 2 alleles compared with wild-type patients（ 11. 8% vs 1. 4%,P =0. 019）. Conclusion In patients with ischemic cerebrovascular disease,the CYP2C19 LOF allele had significant impact on postprocedure clopidogrel HTPR and the prognosis of ISR after PTAS.