The Pharmacogenomic Control of Clopidogrel Response in Acute Coronary Syndromes

急性冠脉综合征中氯吡格雷反应的药物基因组学控制

基本信息

批准号：
8581390
负责人：
Stuart Alexander Scott
金额：
$ 19.45万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581390
关键词：
ABCB1 gene Accounting Adoption Advisory Committees Aftercare Alleles American Ancillary Study Anticoagulants Antiplatelet Drugs Applications Grants Aspirin Award Basic Science Benchmarking Biology Blood Platelets Candidate Disease Gene Cardiology Cardiovascular system Caring Clinical Clinical Research Clinical Sciences Clinical Services Clinical Trials Clinical Trials Design Clinical and Translational Science Awards Collaborations Committee Members Complex Cytochrome P450 DNA Sequence Data Data Analyses Disease Doctor of Medicine Doctor of Philosophy Drug Kinetics Effectiveness Enrollment Environment Enzymes Epidemiologist Equipment Event Faculty Foundations Frequencies Funding Future Gene Frequency Gene Mutation Genes Genetic Genetic Polymorphism Genetic Variation Genetic screening method Genomics Genotype Goals Human Genetics Hybrids Institutes Laboratories Legal patent Medical Genetics Medicine Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Meta-Analysis Molecular Network-based Outcome Outcomes Research Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacogenomics Phenotype Platelet aggregation Play Practice Guidelines Principal Investigator Programmed Instruction Publications Quality Control Research Research Personnel Research Project Grants Resistance Resources Risk Role Sampling Science Serious Adverse Event Single Nucleotide Polymorphism Stents Testing Thrombosis Time Training Translational Research Treatment Efficacy Variant Warfarin acute coronary syndrome base career career development clinically relevant clopidogrel cohort design exome sequencing experience genetic variant genome wide association study genome-wide loss of function medical schools next generation novel patient oriented percutaneous coronary intervention pharmacogenetic testing programs public health relevance response skills standard of care trait uptake

项目摘要

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.

描述（由申请人提供）：候选人：Stuart A. Scott 博士是西奈山基因检测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，他凭借在临床和基础科学方面的培训和经验开发一个专注于转化药物基因组学的研究计划。他之前的药物遗传学研究主要集中在抗凝剂华法林和抗血小板药物氯吡格雷，并且他与人共同撰写了这两种药物的临床药物遗传学实践指南。现在，他正在寻求为期四年的 K23 重点奖，以支持他在完成两年期转化科学领域 KL2 学院学者奖后，将 85% 的临床责任保护时间用于启动全外显子组测序药物基因组学研究项目以及相关的职业发展。职业发展：候选人的长期目标是成为转化药物基因组学研究领域的独立资助的首席研究员。这一目标将通过基于临床和转化科学奖 (CTSA)/药物基因组学研究网络 (PGRN) 的共同指导、协作以及本申请中概述的实践和教学机制来实现。机构环境：西奈山医学院 (MSSM) 的遗传学和基因组科学系是一个混合基础科学和临床部门，提供转化遗传学和基因组科学方面广泛的教学、研究和临床服务项目。 MSSM 基因组学和多尺度生物学研究所是完成现代基因组学研究所需的所有设备和计算支持的中心资源。因此，MSSM 的机构环境非常适合正确执行本申请中概述的研究。研究项目：氯吡格雷和阿司匹林双重抗血小板治疗 (DAPT) 是急性冠脉综合征 (ACS) 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，血小板抑制和临床反应存在显着的个体差异是普遍观察到的。细胞色素 P450-2C19 (CYP2C19) 是参与氯吡格雷生物激活的关键酶，携带 CYP2C19 功能丧失等位基因的患者治疗效果降低，严重不良心血管事件的风险增加。然而，CYP2C19 仅占氯吡格雷反应变异性的约 12%。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，这可能有助于将基因引导的抗血小板治疗纳入常规介入心脏病学实践中以获得更个性化和有效的护理。额外基因和变异的鉴定不仅会影响个性化抗血小板治疗的采用，而且可以为具有可变反应的药物和药物的其他药物基因组学研究提供基准。