Genetics of Cardiotoxic Drug Response

 描述（由申请人提供）：这是波士顿马萨诸塞州总医院心脏电生理学家Michael Rosenberg博士的K23指导患者导向研究职业发展奖的申请。 Rosenberg博士正在寻求成为心律失常遗传学的独立临床研究者。 该奖项将为Rosenberg博士提供必要的支持，以获得以下研究技能：1）了解人类遗传变异及其与复杂和孟德尔性状的关系，2）临床研究设计和实施; 3）大规模数据管理，统计分析和解释的工具。 药物诱导的QT间期延长和导致的致死性心律失常尖端扭转型室性心动过速 (TdP)是导致药物退出市场的头号临床毒性。 最令人担忧的是，这种毒性可能发生在非心脏疾病的药物中，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要求住院一段时间，以监测治疗开始期间的QT间期延长。显然需要对药物诱导的QT间期延长进行更好的风险分层。的可能性 遗传学可用于识别易感个体，这为正在进行的人口研究提供了直接临床应用的独特机会。 心电图QT间期是可遗传的，并且与一般人群中的心律失常和心脏性猝死有分级关系。 最近，35个基因中的68个常见遗传变异预测QT间期的变异性。 先前的研究表明，QT遗传评分的前五分位数预测QT间期的差异为10- 15 ms。这一持续时间长于迫使一些非心脏病药物退出市场的QT间期延长。然而，证明遗传风险可以预测药物诱导的QT间期延长仍然难以捉摸。 Rosenberg博士的研究将侧重于使用从这68种与QT间期相关的常见变异中得出的多基因风险评分来预测药物诱导的QT间期延长，这些患者包括：按基因型选择的健康年轻个体（目标1）、使用电子健康记录挖掘的“真实的虚拟世界人群”（目标2）、正在接受与QT间期延长相关的抗心律失常药物治疗的高风险患者（目标3），以及尖端扭转型室性心动过速致死性心律失常的幸存者（目标4）。通过完成这些目标，Rosenberg博士将确立基因检测在预测药物诱导的QT间期延长中的作用。 这项职业发展奖申请中提出的活动将为Rosenberg博士提供出色的培训，为遗传流行病学的独立研究生涯做准备，同时为常见的心血管疾病带来重要的新见解。

 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.