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: 8532960
• 负责人: Jessica L Mega
• 金额: $ 23.11万
• 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/8532960
• 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.

项目摘要/摘要 研究摘要：硫吡啶氯吡格雷是最常见的药物之一， 这种口服抗血小板剂降低了急性冠状动脉综合征（ACS）中心血管事件的风险 患者。但是，对氯吡格雷的药效学反应在个体之间有所不同，而这些反应使这些反应 血小板抑制程度较小的患者患心血管事件的风险增加。一个潜力 这种可变性的来源是氯吡格雷的代谢，这是一种需要生物转化的促毒剂 成为活性抗血小板化合物。细胞色素P450（CYP）酶在代谢中起作用， 我们最近确定CYP2C19中特定遗传变异的载体（占人群的30％） 活性氯吡格雷代谢物水平较低，血小板抑制减少，不良速率较高 与非携带者相比，心血管事件。 硫烯吡啶的吸收和代谢涉及其他关键蛋白质，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）。 MDR1，CES1和CES2中的遗传变异是否影响药理和 对氯吡格雷或对较新的，第三代硫吡啶prasugrel的临床反应。这个建议 概述了一个科学计划：（1）确定多态性在硫烯吡啶中涉及的基因中的影响 用氯吡格雷治疗的健康受试者中活性药物代谢物水平和血小板抑制的代谢 和prasugrel; （2）评估这些遗传因素对ACS不良心血管结局的影响 接受硫吡啶治疗的患者； （3）进行临床试验以测试遗传变异是否在 CYP2C19和AIM 1和2中确定的CYP2C1可以高于当前建议的 氯吡格雷剂量或用prasugrel治疗。最终，确定影响个体的多态性 对硫吡啶的反应应帮助医生为每个患者选择最佳剂量和药物。 候选人：杰西卡·梅加（Jessica Mega）博士在布里格姆（Brigham）和妇女医院（BWH）和 马萨诸塞州综合医院的心脏病学。在过去的两年中，她参加了 心血管研究培训计划（NHLBI T32 HL07575）进行了临床研究 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 集中于生物统计学和流行病学。她一直在使用生物标志物和遗传信息 了解ACS患者的病理生物学，并评估反应的变异性 药物治疗。此外，她还在临床试验设计和实施方面进行培训。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，以进行临床试验，以进行临床试验 研究使用遗传信息来量身定制药物疗法的应用。 该提案制定了一项培训计划，以指导Mega博士从指导的学员到独立 医师科学家。了解和合并遗传学和临床试验需要发展 高级研究技能集。最初的指导时期将包括与既定导师的培训（Drs。 Eugene Braunwald和Marc Sabatine与Timi研究小组）和多学科咨询委员会 遗传学，药理学，血小板生物学和心血管临床试验的专家。 Mega博士将过渡 当她领导AIM 3中提出的临床试验时，在该奖项的第三年进行科学独立。 环境：BWH的心血管师提供了各种各样的教职员工 从事基本和临床研究活动，该机构致力于鼓励合作。 此外，它的领导力致力于保护Mega博士的研究时间，并促进她的发展 独立的医师科学家。 Mega博士还可以在哈佛学校获得资源 公共卫生，广泛研究所和哈佛大学。 特别是，Mega博士将继续与Timi研究小组一起研究，该小组由Eugene博士创立。 Braunwald并在ACS进行了25年以上的临床试验。该小组由12组组成 医师，包括Marc Sabatine博士，他们拥有使用生物标志物和遗传的丰富经验 信息以评估ACS患者。研究小组还包括项目经理，研究助理， 统计学家和行政助理。 TIMI研究组进行的临床试验提供了大量 详细临床信息的高标准化集合，随机分配到密钥 治疗干预措施，以及中央裁决的仔细的长期评估。血液样本 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 研究小组还提供适当的培训环境，为Mega博士提供领导所需的技能 AIM 3中描述的多中心临床试验。