The Pharmacogenomic Control of Clopidogrel Response in Acute Coronary Syndromes

描述(由申请人提供)： 候选人：斯图尔特·A·斯科特，博士，西奈山基因测试实验室的临床分子遗传学家，获得美国医学遗传学委员会(ABMG)认证，他利用自己在临床和基础科学方面的培训和经验，开发了一项专注于转译药物基因组学的研究计划。他之前的药物遗传学研究集中在抗凝剂华法林和抗血小板药物氯吡格雷上，他与人合著了这两种药物的临床药物遗传学实践指南。他现在寻求一个有针对性的四年K23奖，以支持85%的保护时间从他的临床责任，以启动一个完整的外显子组测序药物基因组学研究项目与相关的职业发展，当他完成他的两年机构KL2学院翻译科学学者奖。 职业发展：候选人的长期目标是成为翻译药物基因组研究领域的一名独立资助的首席研究员。这一目标将通过临床和翻译科学奖(CTSA)/药物基因组学研究网络(PGRN)为基础的共同指导、合作以及本申请中概述的实用和教学机制来实现。 机构环境：西奈山医学院(MSSM)遗传学和基因组科学系是一个混合的基础科学和临床系，提供翻译遗传学和基因组科学方面的基础广泛的教学、研究和临床服务。MSSM基因组和多尺度生物学研究所是完成现代基因组研究所需的所有设备和计算支持的中心资源。因此，MSSM的机构环境是正确执行本申请中概述的研究的理想选择。 研究项目：氯吡格雷和阿司匹林联合应用的双重抗血小板治疗(DAPT)是急性冠脉综合征(ACS)患者和/或接受经皮冠状动脉介入治疗(PCI)患者的标准治疗方案。然而，在血小板抑制和临床反应方面经常观察到显著的个体差异。细胞色素P450-2C19(细胞色素P450-2C19)是氯吡格雷生物激活的关键酶，携带细胞色素P450-2C19功能缺失等位基因的患者治疗效果降低，严重心血管事件的风险增加。然而，在氯吡格雷反应中，CYP2C19只解释了~12%的变异。拟议的研究项目将在精心挑选的接受DAPT治疗的ACS/PCI患者的极端表型队列中使用全外显子组测序和全基因组基因分型，以识别新的遗传变异，这将有助于将基因引导的抗血小板治疗应用于常规介入心脏病学实践，以实现更个性化和有效的护理。附加基因和变异体的识别不仅将影响个体化抗血小板治疗的接受，而且可能为其他药物和不同反应药物的药物基因组学研究提供基准。

DESCRIPTION (provided by applicant): CANDIDATE: Stuart A. Scott, Ph.D., is a clinical molecular geneticist in the Mount Sinai Genetic Testing Laboratory, certified by the American Board of Medical Genetics (ABMG), who has drawn on his training and experience in clinical and basic science to develop a research program focused on translational pharmacogenomics. His previous pharmacogenetics research centered on the anticoagulant warfarin and the antiplatelet clopidogrel, and he has co-authored clinical pharmacogenetic practice guidelines for both of these agents. He now seeks a focused four-year K23 Award to support 85% protected time from his clinical responsibilities to initiate a whole-exome sequencing pharmacogenomics research project with related career development as he completes his two-year Institutional KL2 Faculty Scholar award in translational science. CAREER DEVELOPMENT: The long-term goal of the Candidate is to become an independently funded Principal Investigator in the field of translational pharmacogenomics research. This goal will be accomplished through Clinical and Translational Science Award (CTSA)/Pharmacogenomics Research Network (PGRN)- based co-mentorship, collaboration, and the practical and didactic mechanisms outlined in this application. INSTITUTIONAL ENVIRONMENT: The Department of Genetics and Genomic Sciences at the Mount Sinai School of Medicine (MSSM) is a hybrid basic science and clinical department that offers a broad-based program of instruction, research, and clinical services in translational genetics and genomic sciences. The MSSM Institute for Genomics and Multiscale Biology is a central resource for all the equipment and computational support necessary to accomplish modern genomics research. As such, the institutional environment at MSSM is ideal for the proper execution of the studies outlined in this application. RESEARCH PROJECT: Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is standard of care for patients with acute coronary syndromes (ACS) and/or for those undergoing percutaneous coronary intervention (PCI)~ however, substantial interindividual variability in platelet inhibition and clinical response is commonly observed. Cytochrome P450-2C19 (CYP2C19) is a key enzyme involved in clopidogrel bioactivation and patients who carry CYP2C19 loss-of-function alleles have reduced therapeutic efficacy and increased risks for serious adverse cardiovascular events. However, CYP2C19 only accounts for ~12% of the variability in clopidogrel response. The proposed research project will use whole-exome sequencing and genome-wide genotyping in carefully selected extreme phenotype cohorts of DAPT-treated ACS/PCI patients to identify novel genetic variants, which could facilitate the adoption of genetically guided antiplatelet therapy into routine interventional cardiology practice for more personalized and effective care. The identification of additioal genes and variants will not only influence the uptake of personalized antiplatelet therapy, but could provide a benchmark for other pharmacogenomic studies on drugs and medications with variable responses.