基因多态性对氯吡格雷治疗急性脑梗死有效性影响的研究

发布时间：2018-12-18 16:43

【摘要】：研究背景及目的：脑卒中具有高致残率、高病死率、高复发率的特点，是危害人类生命健康的三大疾病之一。脑梗死在脑卒中占有较高的比例。目前脑梗死最主要的治疗方法为溶栓治疗及抗血小板聚集治疗，而抗血小板聚集治疗在脑梗死的急性期治疗及二级预防中占有更重要的地位。然而，部分患者虽长期、规律的服用抗血小板药物，却仍然有卒中复发的风险。目前，氯吡格雷已经成为目前最广泛应用于临床的抗血小板药物之一，但有文献报道，4-30%的患者服用氯吡格雷无效，此种现象2003年被学者称为“氯吡格雷抵抗”。但氯吡格雷抵抗的发生的机制目前尚不完全清楚，大量研究显示：氯吡格雷的抗血小板疗效可能与其代谢及作用过程中的基因多态性、患者的基础病及合并他汀类降脂药等药物之间的相互作用相关。本研究试图通过氯吡格雷药物代谢及作用过程的基因多态性、患者的基础病以及合并应用他汀类药物等对氯吡格雷治疗急性缺血性卒中有效性的影响作一分析和讨论。研究内容及研究方法：1.患者资料：收集2011年8月至2012年7月我院神经内科收治的发病在72小时以内的急性脑梗死患者。入组标准及排除标准略。2.方法：随机入组，共筛选出动脉硬化性脑血栓形成259例住院患者（男171例，女88例）。给予氯吡格雷75mg/天，治疗前签署知情同意书。治疗开始前及治疗后7天检测ADP诱导的血小板聚集试验，应用血小板聚集率的下降差值来评估氯吡格雷疗效。PCR技术、基因试剂盒和基因序列测定CYP2C19(636GA,681GA)、CYP3A4(894CT)、P2Y12(34CT,52GT)多态性。治疗前、治疗后14、90，180天检测NIHSS和MRS评分。统计方法：两组比较用独立t检验，两组以上采用单因素方差分析，独立危险因素预测应用多元回归分析。研究结果：应用氯吡格雷治疗前后，携带CYP2C19无功能等位基因（*2，*3）的患者ADP诱导的血小板聚集率的下降差值较未携带CYP2C19无功能等位基因（*2，*3）的患者的血小板聚集率的下降差值明显减少(p=0.020，0.016)。在治疗开始后行MRS评分，，统计分析后示3，6个月未携带无功能等位基因的患者预后较携带者好。在6个月时，快代谢型、中间代谢型、慢代谢型三组的卒中复发率无明显差异。单因素及多因素回归分析结果表明CYP2C19可作为氯吡格雷抵抗发生的独立预测因素。结论：CYP2C19基因多态性可对氯吡格雷治疗脑梗死的疗效及脑梗死的预后产生明显的影响，筛查CYP2C19的基因型或许能为神经科医生在脑梗死抗血小板的个体化治疗中提供一定的指导。
[Abstract]:Background and objective: stroke has the characteristics of high disability rate, high fatality rate and high recurrence rate. It is one of the three major diseases endangering human life and health. Cerebral infarction accounts for a high proportion of stroke. At present, thrombolytic therapy and antiplatelet aggregation therapy are the main treatment methods for cerebral infarction, and antiplatelet aggregation therapy plays a more important role in the acute treatment and secondary prevention of cerebral infarction. However, some patients, although long-term, regular use of anti-platelet drugs, but still have the risk of stroke recurrence. At present, clopidogrel has become one of the most widely used antiplatelet drugs in clinical practice, but it has been reported that 4-30% of patients take clopidogrel ineffective, this phenomenon has been referred to as "clopidogrel resistance" in 2003. However, the mechanism of clopidogrel resistance is not fully understood. A large number of studies have shown that the antiplatelet effect of clopidogrel may be related to its metabolism and gene polymorphism during its action. There is a correlation between underlying diseases in patients and drugs such as statins. This study attempts to analyze and discuss the effects of clopidogrel on the efficacy of clopidogrel in the treatment of acute ischemic stroke through gene polymorphisms of clopidogrel metabolism and action process, the underlying diseases of patients and combined use of statins. Research contents and methods: 1. Patient data: from August 2011 to July 2012, patients with acute cerebral infarction within 72 hours were admitted to Department of Neurology in our hospital. Inclusion criteria and exclusion criteria. 2. 2. Methods: 259 inpatients with arteriosclerotic cerebral thrombosis (171 males and 88 females) were randomly selected. Clopidogrel was given 75mg/ days and informed consent was signed before treatment. The platelet aggregation induced by ADP was detected before and 7 days after treatment. The efficacy of clopidogrel was evaluated by the difference of platelet aggregation rate. PCR technique, gene kit and gene sequencing CYP2C19 (636 GAN 681 GA), CYP3A4 (894CT) were used to evaluate the efficacy of clopidogrel. P2Y12 (34CTT 52GT) polymorphism. NIHSS and MRS scores were measured before and 1490180 days after treatment. Statistical methods: two groups were compared by independent t test, two groups by single factor ANOVA, and independent risk factors were predicted by multiple regression analysis. Results: before and after clopidogrel treatment, the difference of platelet aggregation induced by ADP in patients with CYP2C19 nonfunctional allele (* 2) was lower than that without CYP2C19 (* 2). * 3) the decrease difference of platelet aggregation rate was significantly decreased (p0. 020 ~ 0. 016). MRS scores were performed after treatment. Statistical analysis showed that the prognosis of the patients with no functional allele was better than that of the carriers at 3 and 6 months. At 6 months, there was no significant difference in stroke recurrence rate among three groups: fast metabolic type, intermediate metabolic type and slow metabolic type. Univariate and multivariate regression analysis showed that CYP2C19 could be an independent predictor of clopidogrel resistance. Conclusion: the polymorphism of CYP2C19 gene can significantly affect the efficacy of clopidogrel in the treatment of cerebral infarction and the prognosis of cerebral infarction. Screening the genotype of CYP2C19 may provide some guidance for neurologists in the individualized treatment of cerebral infarction antiplatelet.
【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R743.33

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