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

羧酸酯酶 1 (CES1) 在个性化抗血小板治疗中的影响

基本信息

批准号：
9364969
负责人：
JOSHUA PATRICK LEWIS
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9364969
关键词：
Adverse event Affect Agonist Alleles Amino Acid Substitution Angiotensin-Converting Enzyme Inhibitors Antineoplastic Agents Antiplatelet Drugs Area Aspirin Bioinformatics Biological Blood Platelets CYP2C19 gene Carboxylesterase 1 Carboxylic Acids Cardiovascular system Catalytic Domain Clinical Coronary Arteriosclerosis Cross-Over Studies Data Development Enzymes Event Exons Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genotype Glutamic Acid Glycine Hemorrhage Heritability Hydrolysis Individual International Intervention Studies Investigation Medical Meta-Analysis Metabolism Methylphenidate Oseltamivir Outcome Participant Pathologic Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacotherapy Phenotype Physicians Platelet aggregation Positioning Attribute Prevention Prodrugs Randomized Recruitment Activity Recurrence Regimen Research Resistance Risk Single Nucleotide Polymorphism Sulfhydryl Compounds Testing Therapeutic Agents Time Translating United States National Institutes of Health Variant acute coronary syndrome alternative treatment base clinical application clopidogrel cost drug efficacy exome experience flexibility genetic information genetic variant genome sequencing inhibitor/antagonist insight inter-individual variation loss of function loss of function mutation novel percutaneous coronary intervention personalized medicine precision medicine prevent prospective receptor response serine esterase treatment strategy whole genome

Adverse event Affect Agonist Alleles Amino Acid Substitution Angiotensin-Converting Enzyme Inhibitors Antineoplastic Agents Antiplatelet Drugs Area Aspirin Bioinformatics Biological Blood Platelets CYP2C19 gene Carboxylesterase 1 Carboxylic Acids Cardiovascular system Catalytic Domain Clinical Coronary Arteriosclerosis Cross-Over Studies Data Development Enzymes Event Exons Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genotype Glutamic Acid Glycine Hemorrhage Heritability Hydrolysis Individual International Intervention Studies Investigation Medical Meta-Analysis Metabolism Methylphenidate Oseltamivir Outcome Participant Pathologic Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacotherapy Phenotype Physicians Platelet aggregation Positioning Attribute Prevention Prodrugs Randomized Recruitment Activity Recurrence Regimen Research Resistance Risk Single Nucleotide Polymorphism Sulfhydryl Compounds Testing Therapeutic Agents Time Translating United States National Institutes of Health Variant acute coronary syndrome alternative treatment base clinical application clopidogrel cost drug efficacy exome experience flexibility genetic information genetic variant genome sequencing inhibitor/antagonist insight inter-individual variation loss of function loss of function mutation novel percutaneous coronary intervention personalized medicine precision medicine prevent prospective receptor response serine esterase treatment strategy whole genome

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项目摘要

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.

项目摘要冠状动脉疾病患者的医疗管理通常是通过双重来实现的用阿司匹林和氯吡格雷抗血小板治疗，以降低复发性动脉粥样硬化事件的发生率。虽然氯吡格雷通常是有效的，但血小板反应的个体间差异很大已经记录了药物，并且改变了氯吡格雷反应改变的患者的风险增加了经历心血管事件，可能会从替代治疗策略中受益。以前的调查表明，氯吡格雷反应是高度遗传的。但是，除了CYP2C19*2，与氯吡格雷反应可重复相关的遗传因子的鉴定受到限制。我们以前已经表明，在Exon 4的外显子4 羧酸酯酶1（CES1）导致催化甘氨酸（G） - 谷氨酸（E）氨基酸取代位置143（G143E），并且基本影响对氯吡格雷的反应。重要的是，CES1是主要的负责代谢氯吡格雷前药的酶，其中间代谢产物（2-氧化氯粘核），以及最终的生物活性硫醇代谢物成生物非活性羧酸衍生物。因此，遗传影响CES1表达和/或活性的变异可能是氯吡格雷功效的关键决定因素。但是，迄今为止尚无研究表征CES1遗传变异对氯吡格雷的影响回复。在该提议中，我们的总体假设是CES1的全面表征将揭晓新型变体显着影响可变的氯吡格雷反应并使用替代P2Y12 受体抑制剂（即ticagrelor）将逆转这些变体对治疗血小板功能的影响。我们将通过利用现有的外显子组和整个基因组测序数据来检验这一假设为了将CES1的遗传变异优先考虑，然后评估这些变体对抗斑块干预研究的药物基因组学参与者（n = 566）和国际氯吡格雷药物基因组学联盟（n = 5,819）。我们将通过进行氯吡格雷的前瞻性，随机跨界研究（每天75毫克7天）和ticagrelor （每天两次两次，共7天）在健康个体中，CES1基因型（G143E和最显着的在特定目标1中确定的相关变体，每个基因型组30个个体），以评估基因型和药物选择在治疗激动剂刺激的血小板聚集中的相互作用。这些研究将有助于我们关于氯吡格雷耐药性遗传基础的知识并将评估替代性抗血小板治疗对遗传上倾向于的个体的影响氯吡格雷反应改变。了解药物反应变异性和新型治疗的发展策略对于增强个性化医学计划，优化心血管药物疗法至关重要，并最终减少不良患者的结果。