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

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $818,409

## Abstract

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).

## Key facts

- **NIH application ID:** 9921476
- **Project number:** 5R01HL143070-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Christopher Holmes Newton-Cheh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $818,409
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921476

## Citation

> US National Institutes of Health, RePORTER application 9921476, Influence of genetic variation on QT prolongation over the lifecourse and as a cardiotoxic drug response (5R01HL143070-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9921476. Licensed CC0.

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