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

这是PA-13-302研究项目资助金的A0重新提交，题为《基因的影响 QT延长在生命过程中的变化以及作为心脏毒性药物反应的变化。 药物引起的QT间期延长，以及由此导致的致死性心律失常尖端扭转(TDP)，是 导致药物下架的头号临床毒性。多数 关于，这种毒性可能发生在为非心脏疾病开出的药物上，例如 过敏性鼻炎和抑郁症。对于患有心脏疾病的患者，需要使用 抗心律失常药物， 美国食品和药物管理局要求住院一段时间以监测QT过高 启蒙过程中的延长。药物引起的QT明显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 为正在进行的人口研究的直接临床应用提供了一个独特的机会。 心电图QT间期是可遗传的，并与心律失常和 普通人群中的心脏性猝死。最近，在35个基因中有68个常见的遗传变异 是QT间期变异性的预测指标。先前的研究表明，最高五分之一的人 QT遗传积分预测QT间期相差10-15ms。此持续时间长于 QT延长迫使一些非心脏药物退出市场。然而， 关于遗传风险可以预测药物引起的QT延长的证据仍然难以捉摸。在这 研究中，我们将研究遗传学对QT延长的影响。 纵向方法，允许通过使用重复测量来增加精度。我们 我将首先检查常见的QT变异对纵向QT间期的遗传影响 使用Framingham心脏研究总体(目标1)和超过3天的生命周期 开始使用抗心律失常药物的个人住院(目标2)。然后我们将有针对性地执行 对药物引起的QT间期延长的生物学因素进行测序 人群开始服用抗心律失常药物(目标3)。

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).