Genetic Determinants of the Response to Thienopyridine Therapy

噻吩并吡啶治疗反应的遗传决定因素

• 批准号: 8623143
• 负责人: Jessica L Mega
• 金额: $ 23.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623143
• 关键词: ABCB1 gene; Adenosine Diphosphate; Advanced Development; Advisory Committees; Affect; Antiplatelet Drugs; Award; Basic Science; Biology; Biometry; Blinded; Blood Platelets; Blood specimen; CYP2C19 gene; Carboxylic Ester Hydrolases; Cardiac; Cardiology; Cardiovascular system; Cessation of life; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Collection; Commit; Conduct Clinical Trials; Coronary Arteriosclerosis; Cytochrome P450; DNA analysis; Development; Dose; Drug Kinetics; Environment; Enzymes; Epidemiology; Evaluation; Event; Exposure to; Face; Faculty; Fostering; General Hospitals; Generations; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genotype; Hospitals; Individual; Institutes; Institution; Internal Medicine; Intestines; Lead; Leadership; Left; Maintenance; Massachusetts; Measurement; Mediating; Mentors; Metabolic Biotransformation; Metabolism; National Heart, Lung, and Blood Institute; Oral; Outcome; P-Glycoprotein; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Physicians; Plasma; Play; Population; Prodrugs; Proteins; Public Health; Public Health Schools; Randomized; Regimen; Research; Research Activity; Research Training; Resources; Risk; Role; Scientist; Source; Specific qualifier value; Testing; Therapeutic Intervention; Time; Training; Training Programs; Universities; Variant; Woman; absorption; abstracting; acute coronary syndrome; adjudication; carboxylesterase; cardiovascular risk factor; clinically relevant; clopidogrel; cohort; design; efflux pump; experience; genetic analysis; genetic association; genetic variant; high risk; interest; medical schools; member; receptor; response; skills; thienopyridine

PROJECT SUMMARY/ABSTRACT RESEARCH SUMMARY: The thienopyridine clopidogrel is one of the most commonly prescribed medications, and this oral antiplatelet agent reduces the risk of cardiovascular events in acute coronary syndrome (ACS) patients. However, the pharmacodynamic response to clopidogrel varies between individuals, leaving those patients with lesser degrees of platelet inhibition at increased risk of cardiovascular events. One potential source of this variability is the metabolism of clopidogrel, which is a pro-drug requiring biotransformation to become an active antiplatelet compound. Cytochrome P450 (CYP) enzymes play a role in the metabolism, and we have recently identified that carriers of particular genetic variants in CYP2C19 (~30% of the population) have lower active clopidogrel metabolite levels, diminished platelet inhibition, and higher rates of adverse cardiovascular events as compared with non-carriers. There are other key proteins involved in thienopyridine absorption and metabolism, including the intestinal efflux pump P-glycoprotein (encoded by MDR1) and carboxylesterases 1 and 2 (encoded by CES1 and CES2). It remains unknown whether genetic variants in MDR1, CES1, and CES2 impact the pharmacologic and clinical response to clopidogrel or to the newer, third-generation, thienopyridine prasugrel. This proposal outlines a scientific plan to: (1) determine the impact of polymorphisms in genes involved in thienopyridine metabolism on active drug metabolite levels and platelet inhibition in healthy subjects treated with clopidogrel and prasugrel; (2) evaluate the influence of these genetic factors on adverse cardiovascular outcomes in ACS patients treated with thienopyridines; and, (3) conduct a clinical trial to test whether genetic variants in CYP2C19 and those identified in Aims 1 and 2 can be overcome by higher than the currently recommended dose of clopidogrel or treatment with prasugrel. Ultimately, identifying polymorphisms that affect individual responses to thienopyridines should help physicians select the optimal dose and drug for each patient. CANDIDATE: Dr. Jessica Mega trained in Internal Medicine at Brigham and Women's Hospital (BWH) and Cardiology at Massachusetts General Hospital. Over the last two years, she has participated in a cardiovascular research training program (NHLBI T32 HL07575) conducting clinical investigations with the TIMI Study Group (part of BWH and Harvard Medical School) and has earned a Masters in Public Health concentrating in biostatistics and epidemiology. She has been using biomarker and genetic information to understand the pathobiology of ACS patients and to evaluate the variability in the response to pharmacotherapies. Additionally, she has been training in clinical trial design and implementation. Over time, Dr. Mega envisions combining her interests in genetics and ACS clinical trials to conduct clinical trials that investigate the use of genetic information to tailor the application of pharmacotherapies. The proposal sets out a training program to guide Dr. Mega from a mentored trainee to an independent physician-scientist. Understanding and merging genetics and clinical trials requires the development of an advanced set of research skills. The initial mentored period will include training with established mentors (Drs. Eugene Braunwald and Marc Sabatine with the TIMI Study Group) and a multi-disciplinary advisory committee of experts in genetics, pharmacology, platelet biology, and cardiovascular clinical trials. Dr. Mega will transition to scientific independence in year three of the award when she leads the clinical trial set out in Aim 3. ENVIRONMENT: The Cardiovascular Division at BWH offers exposure to a diverse range of faculty members engaged in basic and clinical research activities, and the institution is committed to encouraging collaborations. Moreover, its leadership is dedicated to protecting Dr. Mega's research time and fostering her development as an independent physician-scientist. Dr. Mega will also have access to resources at the Harvard School of Public Health, the Broad Institute, and Harvard University. Specifically, Dr. Mega will continue her research with the TIMI Study Group, which was founded by Dr. Eugene Braunwald and has conducted clinical trials in ACS for more than 25 years. The group consists of 12 physicians, including Dr. Marc Sabatine, who has extensive experience using biomarker and genetic information to evaluate ACS patients. The research group also includes project managers, research assistants, statisticians, and administrative assistants. The clinical trials conducted by the TIMI Study Group provide large cohorts with highly standardized collection of detailed clinical information, randomized assignment to key therapeutic interventions, and careful, long-term evaluations with central adjudication. Blood samples from these trials are available for DNA analysis for the studies outlined in Aims 1 and 2 of this proposal. The TIMI Study Group also offers the appropriate training environment to provide Dr. Mega with the skills needed to lead the multicenter clinical trial described in Aim 3.

项目概要/摘要 研究摘要：噻吩并吡啶氯吡格雷是最常用的处方药物之一， 这种口服抗血小板药物可降低急性冠脉综合征 (ACS) 心血管事件的风险 患者。然而，氯吡格雷的药效学反应因人而异，因此 血小板抑制程度较低的患者发生心血管事件的风险增加。一种潜力 这种变异性的根源在于氯吡格雷的代谢，氯吡格雷是一种前药，需要生物转化才能 成为活性抗血小板化合物。细胞色素 P450 (CYP) 酶在新陈代谢中发挥作用， 我们最近发现了 CYP2C19 特定基因变异的携带者（约占人口的 30%） 活性氯吡格雷代谢物水平较低，血小板抑制作用减弱，不良反应发生率较高 与非携带者相比心血管事件。 还有其他关键蛋白质参与噻吩并吡啶的吸收和代谢，包括肠道 外排泵 P-糖蛋白（由 MDR1 编码）和羧酸酯酶 1 和 2（由 CES1 和 CES2 编码）。 目前尚不清楚 MDR1、CES1 和 CES2 的遗传变异是否会影响药理学和 对氯吡格雷或更新的第三代噻吩并吡啶普拉格雷的临床反应。这个提议 概述了一项科学计划：(1) 确定涉及噻吩并吡啶的基因多态性的影响 接受氯吡格雷治疗的健康受试者的代谢对活性药物代谢水平和血小板抑制的影响 和普拉格雷； (2)评估这些遗传因素对ACS不良心血管结局的影响 用噻吩并吡啶类药物治疗的患者； (3) 进行临床试验以测试基因变异是否存在 CYP2C19 以及目标 1 和 2 中确定的目标可以通过高于当前建议的水平来克服 氯吡格雷剂量或普拉格雷治疗。最终，识别影响个体的多态性 对噻吩并吡啶类药物的反应应有助于医生为每位患者选择最佳剂量和药物。 候选人：杰西卡·梅加 (Jessica Mega) 医生在布莱根妇女医院 (BWH) 接受过内科培训，并在 马萨诸塞州总医院的心脏病学。近两年来，她参加了 心血管研究培训计划（NHLBI T32 HL07575）与 TIMI 研究小组（BWH 和哈佛医学院的一部分）并获得了公共卫生硕士学位 专注于生物统计学和流行病学。她一直在利用生物标记和遗传信息 了解 ACS 患者的病理学并评估对 ACS 患者反应的变异性 药物疗法。此外，她还接受了临床试验设计和实施方面的培训。随着时间的推移， Mega 博士设想将她对遗传学和 ACS 临床试验的兴趣结合起来，进行以下临床试验： 研究利用遗传信息来调整药物疗法的应用。 该提案制定了一个培训计划，指导 Mega 博士从受指导的实习生转变为独立的 医生科学家。理解和融合遗传学和临床试验需要开发一个 先进的研究技能。最初的指导期将包括与既定导师（博士）的培训。 Eugene Braunwald 和 Marc Sabatin 与 TIMI 研究小组）以及多学科咨询委员会 由遗传学、药理学、血小板生物学和心血管临床试验方面的专家组成。梅加博士将转型 在获奖的第三年，当她领导目标 3 中规定的临床试验时，她获得了科学独立性。 环境：BWH 心血管部门为各种教职人员提供接触机会 从事基础和临床研究活动，该机构致力于鼓励合作。 此外，其领导层致力于保护 Mega 博士的研究时间并促进她的发展 一位独立的医师科学家。 Mega 博士还将获得哈佛大学的资源 公共卫生、布罗德研究所和哈佛大学。 具体来说，Mega 博士将与 Eugene 博士创立的 TIMI 研究小组一起继续她的研究 Braunwald 博士在 ACS 领域进行临床试验已超过 25 年。该团体由12人组成 医生，包括 Marc Sabatin 博士，他在使用生物标志物和遗传技术方面拥有丰富的经验 评估 ACS 患者的信息。研究小组还包括项目经理、研究助理、 统计员和行政助理。 TIMI研究组进行的临床试验提供了大量 具有高度标准化的详细临床信息收集、随机分配到关键组的队列 治疗干预，以及中央裁决的仔细、长期评估。血液样本来自 这些试验可用于本提案目标 1 和 2 中概述的研究的 DNA 分析。蒂米 Study Group 还提供适当的培训环境，为 Mega 博士提供领导所需的技能 目标 3 中描述的多中心临床试验。