TY - JOUR
T1 - Genetic Basis and Prognostic Value of Exercise QT Dynamics
AU - Van Duijvenboden, Stefan
AU - Ramírez, Julia
AU - Young, William J.
AU - Mifsud, Borbala
AU - Orini, Michele
AU - Tinker, Andrew
AU - Munroe, Patricia B.
AU - Lambiase, Pier D.
N1 - Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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 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. Genome-wide association studies identified 20 loci, of which 4 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 cardiovascular 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, 1.09 [95% CI, 1.05-1.13], P=2.28×10-5), 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 or ischemia may influence repolarization dynamics. The strong overlap between QT dynamics and resting QT interval loci suggests common biological pathways; however, nonoverlapping loci suggests alternative mechanisms may exist that underlie QT interval dynamics.
AB - 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 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. Genome-wide association studies identified 20 loci, of which 4 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 cardiovascular 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, 1.09 [95% CI, 1.05-1.13], P=2.28×10-5), 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 or ischemia may influence repolarization dynamics. The strong overlap between QT dynamics and resting QT interval loci suggests common biological pathways; however, nonoverlapping loci suggests alternative mechanisms may exist that underlie QT interval dynamics.
KW - cardiovascular disease
KW - exercise
KW - genome-wide association study
KW - mortality
KW - risk factors
UR - http://www.scopus.com/inward/record.url?scp=85089768695&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.119.002774
DO - 10.1161/CIRCGEN.119.002774
M3 - Article
C2 - 32527199
AN - SCOPUS:85089768695
SN - 1942-325X
VL - 13
SP - E002774
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 4
ER -