CYP450s及ABCB1基因多态性与缺血性脑卒中的复发风险的相关性研究

发布时间：2018-12-21 08:50

【摘要】：目的探讨分析福建汉族人群中CYP2C19*2、*3、*17、CYP2C9*3及ABCB1C3435T基因多态性的分布情况，并分析这5个基因多态对服用氯吡格雷的缺血性脑卒中患者脑卒中复发风险的影响。方法采用聚合酶链反应-限制性片断长度多态性技术(PCR-RFLP)及直接测序技术对1000名没有亲缘关系的福建汉族志愿者CYP2C19*2、*3、*17、CYP2C9*3及ABCB1C3435T基因多态位点进行检测，了解其基因多态性分布情况；回顾性收集2011年3月至2013年3月985名就诊于福建医科大学附属第一医院的缺血性脑卒中患者的临床资料，并对其进行门诊、电话随访，，选取规律服用常规治疗剂量的氯吡格雷满一年的患者（n=114名），评估其CYP2C19*2、*3、*17、CYP2C9*3及ABCB1C3435T基因多态性与缺血性脑卒中复发情况的相关性。同时，我们用mRS评分评估其入院时及服药满1年时的功能恢复情况。结果在所筛查1000名健康志愿者中，CYP2C19*2、*3、*17、CYP2C9*3、ABCB1C3435T的频率分别为33.0%、5.75%、0.30%、1.95%、41.85%。根据CYP2C19基因多态位点分型，中间代谢型（*1*2和*1*3）与弱代谢型（*2*2、*2*3）分别占47.7%和14.9%。根据ABCB1C3435T基因多态位点功能代谢分型，高代谢型（CC型）、中等代谢型（CT型）及低代谢型（TT型）分别占32.0%、52.3%、15.7%。在服药满1年的患者中(n=114)，再发缺血性脑卒中23人。弱代谢型较正常代谢型及中间代谢型的脑卒中复发风险高（OR=2.156，P=0.026）；携带有CYP2C19*2弱等位基因的脑卒中复发的风险增高（OR=2.993，P=0.013）；既往有卒中史者更容易发生卒中复发（OR=4.146；P=0.019）。然而，CYP2C19*3、*17,CYP2C9*3及ABCB1C3435T基因多态性与脑卒中复发风险无显著相关。结论氯吡格雷药物基因CYP2C19、CYP2C9在人群分布上存在种族/地区差异，福建汉族人群中该多态分布与国内北方汉族、南方汉族人群及东亚、日本人群没有明显差异。在对缺血性脑卒中病人的随访中发现，CYP2C19*2的基因多态性是脑卒中复发的独立危险因素，CYP2C19*3、CYP2C19*17、CYP2C9*3及ABCB1基因多态性与脑卒中复发无显著相关。
[Abstract]:Objective to investigate the distribution of CYP2C19*2,*3,*17,CYP2C9*3 and ABCB1C3435T gene polymorphisms in Fujian Han population and their effects on the risk of stroke recurrence in patients with ischemic stroke taking clopidogrel. Methods Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing technique were used to study CYP2C19*2,*3,*17, in 1000 unrelated Fujian Han Chinese volunteers. The polymorphic loci of CYP2C9*3 and ABCB1C3435T genes were detected to find out the distribution of gene polymorphism. The clinical data of 985 patients with ischemic stroke in the first affiliated Hospital of Fujian Medical University from March 2011 to March 2013 were retrospectively collected. The relationship between CYP2C19*2,*3,*17,CYP2C9*3 and ABCB1C3435T gene polymorphisms and the recurrence of ischemic stroke was evaluated in 114 patients (n = 114) who regularly took clopidogrel for one year. At the same time, the mRS score was used to evaluate the functional recovery at admission and at the end of 1 year. Results among the 1000 healthy volunteers screened, the frequency of CYP2C19*2,*3,*17,CYP2C9*3,ABCB1C3435T was 33. 0 and 5. 75, and 0. 30, 1. 95 and 41. 85, respectively. According to the polymorphic loci of CYP2C19 gene, the intermediate metabolic type (* 1t2) and the weak metabolic type (* 2) accounted for 47. 7% and 14. 9%, respectively. According to the functional metabolic classification of polymorphic loci of ABCB1C3435T gene, high metabolic type (CC type), moderate metabolic type (CT type) and low metabolic type (TT type) accounted for 32.0% and 52.3% respectively. Among the patients who had taken the drug for more than one year (n = 114), 23 patients had recurrent ischemic stroke. The risk of stroke recurrence was higher in the weakly metabolized type than in the normal metabolic type and intermediate metabolic type (OR=2.156,P=0.026), and in the stroke with weak CYP2C19*2 allele (OR=2.993,P=0.013). Stroke recurrence (OR=4.146;P=0.019) is more likely in patients with a history of stroke. However, CYP2C19*3,*17,CYP2C9*3 and ABCB1C3435T gene polymorphisms were not significantly associated with stroke recurrence risk. Conclusion the distribution of clopidogrel drug gene CYP2C19,CYP2C9 is different in population. There is no significant difference in the distribution of clopidogrel gene CYP2C19,CYP2C9 between Fujian Han population and northern Han population, southern Han population, East Asian population and Japanese population. In the follow-up of ischemic stroke patients, it was found that CYP2C19*2 gene polymorphism was an independent risk factor for stroke recurrence, while CYP2C19*3,CYP2C19*17,CYP2C9*3 and ABCB1 gene polymorphisms were not significantly associated with stroke recurrence.
【学位授予单位】：福建医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R743.3

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