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

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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).