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Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval
Julia Ramírez1, Stefan van Duijvenboden1, William J Young2
1Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.
American Journal of Human Genetics
|May 11, 2020
Summary
Genome-wide association studies identified 32 genetic loci influencing the T-peak-to-Tend (Tpe) interval, a key predictor of sudden cardiac death risk. These findings illuminate genetic mechanisms of ventricular repolarization and excitability.
Area of Science:
- Cardiovascular Genetics
- Electrophysiology
- Genomics
Background:
- Sudden cardiac death accounts for half of all cardiovascular disease deaths.
- The T-peak-to-Tend (Tpe) interval and its heart rate response are crucial risk predictors for arrhythmias.
- Limited understanding exists regarding the electrophysiological mechanisms underlying Tpe-based risk stratification.
Purpose of the Study:
- To investigate the genetic underpinnings of resting Tpe and Tpe response to exercise and recovery.
- To identify genetic variants associated with ventricular repolarization and excitability.
Main Methods:
- Genome-wide association studies (GWASs) were performed on approximately 30,000 individuals from UK Biobank.
- Replication analyses were conducted in independent cohorts totaling over 60,000 individuals.
- Sex-specific analyses were incorporated to identify additional genetic loci.
Main Results:
- 32 loci for resting Tpe, 3 for Tpe response to exercise, and 3 for Tpe response to recovery were identified.
- Fifteen and one single-nucleotide variants for resting Tpe and Tpe response to exercise were formally replicated.
- Seven additional loci were identified through sex-specific analyses, impacting ventricular repolarization, conduction, and contraction.
Conclusions:
- This study identifies numerous genetic loci associated with Tpe intervals, providing insights into ventricular repolarization.
- The findings highlight the genetic basis of Tpe and its dynamic changes, offering potential targets for arrhythmia risk stratification.
- Unveiled candidate genes and biological mechanisms contribute to understanding ventricular excitability and sudden cardiac death.
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