Van Duijvenboden, S;
Ramírez, J;
Young, WJ;
Mifsud, B;
Orini, M;
Tinker, A;
Munroe, PB;
(2020)
Genetic Basis and Prognostic Value of Exercise QT Dynamics.
Circulation: Genomic and Precision Medicine
, 13
(4)
, Article e002774. 10.1161/CIRCGEN.119.002774.
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Abstract
Background - Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated. / Methods - QT dynamics during exercise and recovery were derived in 56,643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association studies (GWAS) were conducted to identify genetic variants and bioinformatics analyses were performed to prioritize candidate genes. The prognostic value of QT dynamics was evaluated for cardiovascular events (death or hospitalization) and all-cause mortality. / Results - Heritability of QT dynamics during exercise and recovery were 10.7% and 5.4% respectively GWASs identified 20 loci, of which four loci included genes implicated in mendelian long QT syndrome. Five loci did not overlap with previously reported resting QT interval loci, candidate genes included KCNQ4 and KIAA1755. Genetic risk scores were not associated with CV events in 357,882 unrelated individuals from UK Biobank. We also did not observe associations of QT dynamics during exercise and recovery with cardiovascular events. Increased QT dynamics during recovery was significantly associated with all-cause mortality in the univariate Cox regression analysis (hazard ratio [HR]: 1.09, 95% confidence interval [CI]: 1.05-1.13, P=2.28 x 10-5), but the association was not significant after adjusting for clinical risk factors. / Conclusions - QT interval dynamics during exercise and recovery are heritable markers but do not carry independent prognostic information for clinical outcomes in the UK Biobank, a population-based cohort. Their prognostic importance may relate to cardiovascular disease cohorts where structural heart disease and/or ischaemia may influence repolarization dynamics. The strong overlap between QT dynamics and resting QT interval loci suggests common biological pathways, however non-overlapping loci suggests alternative mechanisms may exists that underlie QT interval dynamics.
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