Genetics of Cardiotoxic Drug Response

心脏毒性药物反应的遗传学

• 批准号: 9116279
• 负责人: Michael A Rosenberg
• 金额: $ 0.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116279
• 关键词: Acute; Admission activity; Adverse effects; Allergic rhinitis; Anti-Arrhythmia Agents; Area; Arrhythmia; Award; Blood specimen; Boston; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Clinical; Clinical Investigator; Clinical Research; Complex; Computerized Medical Record; DNA; Development; Electronic Health Record; Enrollment; Excision; General Hospitals; General Population; Genes; Genetic; Genetic Risk; Genetic Variation; Genetic screening method; Genotype; Health; Hospitalization; Hospitals; Human Genetics; Individual; Inpatients; Investigation; K-Series Research Career Programs; Marketing; Massachusetts; Mental Depression; Mentored Patient-Oriented Research Career Development Award; Mentorship; Mining; Monitor; Moxifloxacin; Outpatients; Patients; Pharmaceutical Preparations; Placebos; Population; Preparation; Recruitment Activity; Research; Research Design; Rest; Risk; Role; Statistical Data Interpretation; Stratification; Subgroup; Survivors; Testing; Time; Torsades de Pointes; Toxic effect; Training; United States Food and Drug Administration; Variant; career; clinical application; data management; dofetilide; drug market; genetic epidemiology; genetic predictors; genetic variant; healthy volunteer; high risk; insight; millisecond; novel therapeutics; response; skills; sudden cardiac death; tool; trait

 DESCRIPTION (provided by applicant): This is the application for the K23 Mentored Patient-oriented Research Career Development Award for Dr. Michael Rosenberg, a cardiac electrophysiologist at Massachusetts General Hospital, Boston. Dr. Rosenberg is seeking to become an independent clinical investigator in genetics of cardiac arrhythmias. This award will provide Dr. Rosenberg with support necessary to acquire the following research skills: 1) Understanding of human genetic variation and its relationship to complex and Mendelian traits, 2) Clinical study design and implementation; and 3) Tools of large-­‐scale data management, statistical analysis, and interpretation. Drug-­‐induced QT-­‐interval prolongation, and resultant lethal arrhythmia torsade de pointes (TdP), is the number one clinical toxicity leading to removal of medications from the market. Most concerning, this toxicity can occur with medications prescribed for noncardiac conditions, such as allergic rhinitis and depression. For patients with cardiac conditions that require use of antiarrhythmic medications, such as dofetilide, the U.S. Food and Drug Administration mandates a period of hospitalization to monitor for excess QT prolongation during initiation. Better risk stratification is clearly needed for drug-­‐induced QT prolongation. The possibility that genetics might be used to identify susceptible individuals presents a unique opportunity for direct clinical application from ongoing population studies. The electrocardiographic QT interval is heritable, and has a graded relationship to arrhythmias and sudden cardiac death in the general population. Recently, 68 common genetic variants in 35 genes were predictive of variability in QT duration. Prior studies had shown that the top quintile of a QT genetic score predicted a 10-­‐15ms difference in QT interval. This duration is longer than the QT prolongation that forced some non-­‐cardiac medications from the market. However, the demonstration that genetic risk can predict drug-­‐induced QT prolongation remains elusive. Dr. Rosenberg's research will focus on the use of a polygenic risk score derived from these 68 common variants associated with QT interval to predict drug-­‐induced QT prolongation in healthy young individuals selected by genotype (Aim 1), in 'real-­‐world populations' mined using electronic health records (Aim 2), in high-­‐risk patients being administered anti-­‐arrhythmics associated with QT prolongation (Aim 3), and in survivors of torsade de pointes lethal arrhythmias (Aim 4). Through completion of these aims, Dr. Rosenberg will establish the role of genetic testing in predicting drug-­‐induced QT prolongation. The activities proposed in this Career Development Award application will provide Dr. Rosenberg with outstanding training in preparation for an independent research career in genetic epidemiology, and at the same time, bring important new insights into common cardiovascular disease.

 描述(由申请人提供)：这是波士顿马萨诸塞州综合医院的心脏电生理学家Michael Rosenberg博士申请K23导师以患者为导向的研究职业发展奖。罗森博格博士正在寻求成为心律失常遗传学领域的一名独立临床研究员。该奖项将为罗森博格博士提供必要的支持，以获得以下研究技能：1)了解人类基因变异及其与复杂和孟德尔特征的关系；2)临床研究的设计和实施；3)大规模数据管理、统计分析和解释的工具。 药物引起的QT间期延长和致死性心律失常尖端扭转性心动过速 (TDP)是导致药物下架的头号临床毒性。最令人担忧的是，这种毒性可能发生在为非心脏疾病开出的药物上，如过敏性鼻炎和抑郁症。对于需要使用抗心律失常药物(如多非利特)的心脏病患者，美国食品和药物管理局(FDA)要求住院一段时间，以监测启动期间QT间期的过度延长。药物引起的QT延长显然需要更好的风险分层。这种可能性 遗传学可能被用来识别易感个体，这为正在进行的人口研究直接临床应用提供了一个独特的机会。在普通人群中，心电图QT间期是可遗传的，与心律失常和心脏性猝死有等级关系。最近，35个基因中的68个常见遗传变异可以预测QT间期的变异性。先前的研究表明，QT遗传分数的前五分之一预示着QT间期有10-15毫秒的差异。这一持续时间比迫使一些非心脏药物退出市场的QT延长要长。然而，遗传风险可以预测药物诱导的QT延长的证据仍然难以捉摸。罗森博格博士的研究将侧重于使用从这68个与QT间期相关的常见变异中得出的多基因风险分数来预测按基因选择的健康年轻个体(目标1)、使用电子健康记录挖掘的“现实世界人群”(目标2)、正在接受与QT延长相关的抗心律失常药物的高危患者(目标3)以及尖端扭转性致死性心律失常的幸存者(目标4)中药物诱导的QT延长。通过完成这些目标，罗森博格博士将确立基因测试在预测药物诱导的QT延长中的作用。 这份职业发展奖申请书中提出的活动将为罗森博格博士提供出色的培训，为他在遗传流行病学方面的独立研究生涯做准备，同时为常见心血管疾病带来重要的新见解。