Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA040

Poster Communications

Sixteen loci identified for T-wave morphology changes in response to exercise and recovery from UK Biobank implicate genes governing ventricular repolarization

J. Ramírez1,2, S. van Duijvenboden2,1, M. Orini3,4, A. Tinker1,5, P. D. Lambiase2,3, P. B. Munroe1,5

1. William Harvey Research Institute, Queen Mary University London, London, London, United Kingdom. 2. Institute of Cardiovascular Science, University College London, London, London, United Kingdom. 3. Barts Heart Centre, St Bartholomews Hospital, London, London, United Kingdom. 4. Mechanical Engineering Department, University College London, London, London, United Kingdom. 5. NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, London, United Kingdom.

Background: The T-wave morphology restitution (TMR) index, quantifying the variations in the morphology of the T-wave in response to variations in heart rate (HR) have been shown to be strongly associated with increased arrhythmic risk leading to sudden cardiac death in chronic heart failure patients [1, 2]. Currently, the genetic basis of TMR remains to be elucidated. The aim of this study was to discover single-nucleotide polymorphisms (SNPs) associated with TMR. Methods: 1-lead ECG recordings of 52,330 participants of European ancestry from the UK Biobank study who had an exercise stress test were analysed. The study has approval from the Ethics Committee and all participants provided informed consent. The test used a bicycle ergometer and included six minutes of graded cycling exercise and 1-minute recovery [3]. Two TMR phenotypes were derived, quantifying the T-wave morphology changes between resting and peak exercise, and , measured between peak exercise and 50 s post-exercise. We performed a discovery genome-wide association studies (GWASs) for each phenotype in 30,000 individuals and a validation experiment in the remaining 22,330 samples. We also conducted a GWAS in the full data set, all from UK Biobank. Results: Four (RNF207, KCNQ1, SOX5 and KCNJ2) and three (NOS1AP, KCNQ1 and SOX5) loci for and , respectively, formally replicated. In the full data set GWAS, four further loci for (NOS1AP, SCN5A/SCN10A, PREP and KCNH2) and five for (SSBP3, SCN10A, LINC01213, CAMK2D and KLF12) were genome-wide significant (P ≤ 5 × 10−8). In total, we discovered 16 loci, with four being common across traits. A large proportion of the identified loci map to genes functionally related to ventricular repolarization. Conclusion: Our findings demonstrate the genetic contribution of the response of T-wave morphology to changes in HR, and indicate shared physiological mechanisms with QT interval. Future studies will evaluate the contribution of TMR and the associated genes to cardiovascular risk prediction.

Where applicable, experiments conform with Society ethical requirements