The Impact of Carboxylesterase 1 ( CES1 ) in Personalized Antiplalet Therapy

项目摘要 冠状动脉疾病患者的医疗管理最常见的是通过双重 用阿司匹林和氯吡格雷进行抗血小板治疗，以降低动脉粥样硬化血栓形成事件的复发率。 虽然氯吡格雷通常是有效的，但血小板对氯吡格雷的反应在个体间存在很大差异。 已经有文献记载，氯吡格雷反应改变的患者， 发生心血管事件，可能受益于替代治疗策略。先前 研究表明氯吡格雷的反应是高度可遗传的;然而，除了CYP 2C 19 *2， 与氯吡格雷反应相关的遗传因素的鉴定是有限的。 我们以前已经证明，在外显子4的错义功能丧失单核苷酸多态性（SNP）， 羧酸酯酶1（CES 1）导致催化位点甘氨酸（G）-谷氨酸（E）氨基酸取代， 位置143（G143 E），并显著影响对氯吡格雷的反应。重要的是，CES 1是主要的 负责代谢氯吡格雷前药、其中间代谢物（2-氧代-氯吡格雷）的酶， 并将最终的生物活性硫醇代谢物转化为生物学上无活性的羧酸衍生物。因此，基因 影响CES 1表达和/或活性的变异可能是氯吡格雷疗效的关键决定因素。 然而，迄今为止还没有研究表明CES 1基因变异对氯吡格雷的影响 反应在这个提议中，我们的总体假设是，CES 1的全面表征将揭示 显著影响可变氯吡格雷反应的新变体和替代P2 Y12的使用 受体抑制剂（即替格瑞洛）将逆转这些变体对治疗中血小板功能的作用。我们 我将利用现有的外显子组和全基因组测序数据在5,000个人中测试这一假设 从生物信息学上优先考虑CES 1中的遗传变异，然后评估这些变异对 抗血小板药物基因组学干预研究（N = 566）受试者中氯吡格雷的疗效， 国际氯吡格雷药物基因组学联盟（N = 5，819）。我们将扩展这些发现， 对氯吡格雷（每天75毫克，持续7天）和替格瑞洛进行前瞻性、随机交叉研究 (90根据CES 1基因型（G143 E和最显著 在特定目标1中鉴定的相关变体，每个基因型组30个个体），以评估 基因型和药物选择对治疗中激动剂刺激血小板聚集的相互作用这些 研究将有助于我们了解氯吡格雷抵抗的遗传基础 并将评估替代抗血小板治疗对遗传易感个体的影响， 氯吡格雷反应改变。了解药物反应变异性和新治疗的开发 战略对于加强个性化医疗计划，优化心血管药物治疗， 并最终减少患者的不良结果。

PROJECT SUMMARY Medical management of coronary artery disease patients is most commonly achieved through dual antiplatelet therapy with aspirin and clopidogrel in order to reduce rates of recurrent atherothrombotic events. While clopidogrel is generally effective, substantial inter-individual variation in platelet response to this medication has been documented and patients who have altered clopidogrel response have increased risk of experiencing a cardiovascular event and would likely benefit from alternative treatment strategies. Previous investigations have shown that clopidogrel response is highly heritable; however, apart from CYP2C19*2, identification of genetic factors that are reproducibly associated with clopidogrel response has been limited. We have previously shown that a missense loss-of-function single nucleotide polymorphism (SNP) in exon 4 of carboxylesterase 1 (CES1) results in a catalytic site glycine (G)-to-glutamic acid (E) amino acid substitution at position 143 (G143E) and substantially impacts response to clopidogrel. Importantly, CES1 is the primary enzyme responsible for metabolizing the clopidogrel prodrug, its intermediate metabolite (2-oxo-clopidogrel), and the final bioactive thiol metabolite into biologically inactive carboxylic acid derivatives. Therefore, genetic variation affecting CES1 expression and/or activity is likely to be a critical determinant of clopidogrel efficacy. However, no investigation to date has characterized the impact of genetic variation in CES1 on clopidogrel response. In this proposal, our overall hypothesis is that comprehensive characterization of CES1 will unveil novel variants that significantly impact variable clopidogrel response and that use of an alternative P2Y12 receptor inhibitor (i.e. ticagrelor) will reverse the effect of these variants on on-treatment platelet function. We will test this hypothesis by leveraging existing exome and whole genome sequencing data in 5,000 individuals to bioinformatically prioritize genetic variation in CES1 and then assess the impact of these variants on clopidogrel efficacy in participants of the Pharmacogenomics of Anti-Platelet Intervention Study (N = 566) and International Clopidogrel Pharmacogenomics Consortium (N = 5,819). We will extend these findings by performing a prospective, randomized crossover study of clopidogrel (75 mg per day for 7 days) and ticagrelor (90 mg twice daily for 7 days) in healthy individuals by CES1 genotype (G143E and the most significantly associated variant identified in Specific Aim 1, 30 individuals per genotype group) in order to assess the interaction of genotype and drug choice on on-treatment agonist-stimulated platelet aggregation. These studies will contribute to our knowledge regarding the genetic underpinnings underlying clopidogrel resistance and will assess the impact of alternative antiplatelet therapy in individuals who are genetically predisposed to altered clopidogrel response. Understanding drug response variability and the development of novel treatment strategies is critical to enhance personalized medicine initiatives, optimize cardiovascular pharmacotherapy, and ultimately reduce adverse patient outcomes.