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: 8045363
• 负责人: Jessica L Mega
• 金额: $ 13.7万
• 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 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045363
• 关键词: ABCB1 gene; Adenosine Diphosphate; Advanced Development; Advisory Committees; Affect; Antiplatelet Drugs; Award; Basic Science; Biological Markers; 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 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; public health relevance; receptor; response; skills; thienopyridine

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: NARRATIVE Patients with particular genetic variants may not optimally respond to the thienopyridine clopidogrel (a widely- used antiplatelet medication in individuals with coronary artery disease) and therefore face a higher risk of having a major cardiac event. Identifying these genetic variants that impact the response to thienopyridine therapy and determining ways to overcome them should help physicians select the right drug and dose for each patient with coronary artery disease.

描述（由申请人提供）：项目摘要/摘要研究摘要：硫吡啶氯吡格雷是最常见的处方药之一，这种口腔抗血小板剂降低了急性冠状动脉综合征（ACS）患者心血管事件的风险。然而，对氯吡格雷的药效反应在个体之间有所不同，使那些患有较小程度的血小板抑制作用的患者以增加心血管事件的风险增加。这种可变性的潜在来源是氯吡格雷的代谢，这是一种需要生物转化成为活性抗血小板化合物化合物的前药。细胞色素P450（CYP）酶在代谢中发挥作用，我们最近确定，CYP2C19中特定遗传变异的载体（占人群的约30％）具有较低的活性氯吡格雷代谢物水平，与非官员相比，与不良心脏病事件相比，血小板抑制降低，较高的速率。硫烯吡啶吸收和新陈代谢还涉及其他关键蛋白质，包括肠外排泵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对氯吡格雷的药物和临床反应，或对较新的，第三代硫烯吡啶prasugrel影响。该提议概述了一个科学计划：（1）确定硫烯吡啶代谢对活性药物代谢物水平的基因中多态性的影响，并在用氯吡格雷和prasugrel治疗的健康受试者中进行活性药物代谢水平和血小板抑制； （2）评估这些遗传因素对接受硫烯吡啶治疗的ACS患者的心血管不良结局的影响； （3）进行临床试验，以测试CYP2C19和AIM 1和2中鉴定的遗传变异是否可以通过高于当前建议的氯吡格雷剂量或用prasugrel治疗的遗传变异。最终，识别影响对硫吡啶的个人反应的多态性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）博士在杨百翰（Brigham）和妇女医院（BWH）和马萨诸塞州综合医院的心脏病学接受了内科培训。在过去的两年中，她参加了一项心血管研究培训计划（NHLBI T32 HL07575），该计划与TIMI研究小组（BWH和Harvard Medical School的一部分）进行了临床研究，并赢得了公共卫生的硕士学位，专注于生物统计学和病因学。她一直在使用生物标志物和遗传信息来了解ACS患者的病理生物学，并评估对药物疗法反应的可变性。此外，她还在临床试验设计和实施方面进行培训。随着时间的流逝，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，以调查使用遗传信息来量身定制药物治疗的应用。该提案制定了一项培训计划，以指导Mega博士从受过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一系列先进的研究技能。最初的指导时期将包括与既定导师（Eugene Braunwald博士和TIMI研究小组的Marc Sabatine博士）以及遗传学，药理学，血小板生物学和心血管临床临床试验专家的多学科咨询委员会。 Mega博士将在AIM 3中领导临床试验时，将在奖项​​的第三年过渡到科学独立性。环境：BWH的心血管部门提供了从事基础研究和临床研究活动的各种教职员工，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，并促进她作为独立医师科学家的发展。 Mega博士还可以在哈佛大学公共卫生学院，布罗德研究所和哈佛大学获得资源。具体来说，Mega博士将继续与Timi研究小组进行研究，该小组由Eugene Braunwald博士创立，并在ACS中进行了25年以上的临床试验。该小组由12位医生组成，其中包括Marc Sabatine博士，他们使用生物标志物和遗传信息来评估ACS患者有丰富的经验。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研究小组进行的临床试验提供了大型队列，并收集了高度标准化的详细临床信息，随机分配到关键的治疗干预措施，并通过中央裁决进行了仔细的长期评估。这些试验中的血液样本可用于DNA分析，用于本提案的目标1和2中概述的研究。 Timi研究小组还提供了适当的培训环境，为Mega博士提供了领导AIM 3中描述的多中心临床试验所需的技能。 公共卫生相关性：具有特定遗传变异的叙事患者可能无法最佳地反应噻吩吡啶氯吡格雷（冠状动脉疾病患者中广泛使用的抗血小板药物），因此面临更高的心脏事件风险。确定影响对硫烯吡啶疗法反应的这些遗传变异，并确定克服它们的方法，应帮助医生为每个患有冠状动脉疾病的患者选择正确的药物和剂量。

项目成果

Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.

• DOI: 10.1016/s0140-6736(10)61273-1
• 发表时间: 2010-10-16
• 期刊: LANCET
• 影响因子: 168.9
• 作者: Mega, Jessica L.;Close, Sandra L.;Wiviott, Stephen D.;Shen, Lei;Walker, Joseph R.;Simon, Tabassome;Antman, Elliott M.;Braunwald, Eugene;Sabatine, Marc S.
• 通讯作者: Sabatine, Marc S.

Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.

• DOI: 10.1001/jama.2010.1543
• 发表时间: 2010-10-27
• 期刊: JAMA
• 作者: Mega JL;Simon T;Collet JP;Anderson JL;Antman EM;Bliden K;Cannon CP;Danchin N;Giusti B;Gurbel P;Horne BD;Hulot JS;Kastrati A;Montalescot G;Neumann FJ;Shen L;Sibbing D;Steg PG;Trenk D;Wiviott SD;Sabatine MS
• 通讯作者: Sabatine MS