Influence of genetic variation on QT prolongation over the lifecourse and as a cardiotoxic drug response

遗传变异对整个生命过程中 QT 延长的影响以及作为心脏毒性药物反应的影响

• 批准号: 10246254
• 负责人: Christopher Holmes Newton-Cheh
• 金额: $ 68.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246254
• 关键词: Allergic rhinitis; Arrhythmia; Binding; Bioinformatics; Biological; Biological Factors; Cardiac; Cardiotoxicity; Cardiovascular system; Clinic; Clinical; Code; Colorado; Complex; Complex Genetic Trait; DNA; Drug Exposure; Drug Monitoring; Drug Prescriptions; Electrophysiology (science); Epidemiology; Excision; Exposure to; Framingham Heart Study; General Hospitals; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genotype; Heritability; Hospitalization; Individual; International; Investigation; Longitudinal Studies; Massachusetts; Measurement; Measures; Medical Genetics; Mental Depression; Methodology; Monitor; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Population Study; Public Health; Research Personnel; Research Project Grants; Rest; Risk; Risk Factors; Risk-Benefit Assessment; Role; Running; Sotalol; Testing; Therapeutic; Time; Torsades de Pointes; Toxic effect; United States Food and Drug Administration; Universities; Variant; Withdrawal; base; clinical application; clinical risk; cohort; community setting; deep sequencing; dofetilide; drug market; genetic architecture; genetic testing; genetic variant; genome wide association study; improved; novel; novel therapeutics; pre-clinical; prospective; rare variant; response; risk prediction model; risk stratification; screening; side effect; study population; sudden cardiac death; targeted sequencing; trait

This is the A0 re-submission for the PA-13-302 Research Project Grant titled “Influence of genetic variation on QT prolongation over the lifecourse and as a cardiotoxic drug response.” 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, 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. In this investigation, we will examine the impact of genetics on QT prolongation through application of longitudinal methodologies, which allow for added precision through use of repeated measures. We will first examine the genetic impact of common QT variants on the longitudinal QT interval over the lifecourse using the Framingham Heart Study population (Aim 1) and over the 3-day hospitalization of individuals initiated on antiarrhythmics (Aim 2). We will then perform targeted sequencing to identify biological factors involved in drug-induced QT prolongation in the population initiated on antiarrhythmics (Aim 3).

这是PA-13-302研究项目资助的A0重新提交，标题为“遗传因素的影响”。 QT间期延长的变化和心脏毒性药物反应。” 药物诱导的QT间期延长，以及由此导致的致死性心律失常尖端扭转型室性心动过速（TdP）， 导致药物从市场上撤下的头号临床毒性。 最 值得注意的是，这种毒性可能发生在非心脏疾病的药物中，例如 过敏性鼻炎和抑郁症 对于患有心脏病的患者， 抗疟疾药物 美国美国食品和药物管理局要求住院一段时间以监测QT间期延长 启动期间延长。对于药物诱导的QT，显然需要更好的风险分层 延长。 遗传学可能被用来识别易感个体的可能性 为正在进行的人群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，与心律失常有分级关系， 心脏性猝死 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遗传评分预测QT间期差异为10- 15 ms。 此持续时间长于 QT间期延长迫使一些非心脏药物退出市场。 但 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。 在这 研究中，我们将通过应用 纵向方法，通过使用重复测量可以提高精度。 我们 将首先检查常见QT变异对纵向QT间期的遗传影响， 使用Frachial Heart研究人群（目标1）和3天内的生命过程 开始服用抗抑郁药的个人住院治疗（目标2）。然后我们将有针对性地 测序，以确定参与药物诱导的QT间期延长的生物学因素， 开始服用抗抑郁药的人群（目标3）。