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.

中文翻译：

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运动 QT 动力学的遗传基础和预后价值。

背景：对心率的异常 QT 间期反应（QT 动力学）是患者心血管疾病的独立风险预测因子，但尚未研究其在基于人群的队列中的遗传基础和预后价值。方法：运动和恢复期间的 QT 动力学来自英国生物银行的 56 643 个人，没有心血管事件史。进行全基因组关联研究以识别遗传变异，并进行生物信息学分析以优先考虑候选基因。对心血管事件（死亡或住院）和全因死亡率评估 QT 动力学的预后价值。结果：运动和恢复期间 QT 动力学的遗传率分别为 10.7% 和 5.4%。全基因组关联研究确定了 20 个基因座，其中4个位点包含与孟德尔长QT综合征相关的基因。五个基因座与先前报道的静息 QT 间期基因座不重叠；包括候选基因KCNQ4和KIAA1755。在来自英国生物银行的 357 882 名无关个体中，遗传风险评分与心血管事件无关。我们也没有观察到运动和恢复期间 QT 动力学与心血管事件的关联。在单变量 Cox 回归分析中，恢复期间 QT 动态增加与全因死亡率显着相关（风险比，1.09 [95% CI，1.05–1.13]，P =2.28×10 ^-5)，但在调整临床危险因素后，相关性不显着。结论：运动和恢复期间的 QT 间期动态是可遗传的标志物，但在英国生物银行（一个基于人群的队列）中不携带临床结果的独立预后信息。它们的预后重要性可能与心血管疾病队列有关，其中结构性心脏病或缺血可能影响复极动力学。QT 动力学和静息 QT 间期位点之间的强烈重叠表明共同的生物学途径；然而，非重叠位点表明可能存在替代的机制作为 QT 间期动态的基础。