Genetic Basis and Prognostic Value of Exercise QT Dynamics
Genetic Basis and Prognostic Value of Exercise QT Dynamics
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DOI：
10.1161/circgen.119.002774
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发表时间：
2020-08-01
影响因子：
7.4
通讯作者：
Lambiase, Pier D.
中科院分区：
文献类型：
--
作者：
van Duijvenboden, Stefan;Ramirez, Julia;Lambiase, Pier D.
背景：QT间期对心率的异常反应(QT动力学)是患者心血管疾病的独立危险预测因子，但其遗传学基础和人群队列的预后价值尚未被研究。方法：对来自英国生物库的56643名无心血管事件史的受试者进行运动和康复时的QT间期离散度分析。进行了全基因组关联研究以确定遗传变异，并进行了生物信息学分析以确定候选基因的优先顺序。评价QT动态变化对心血管事件(死亡或住院)和全因死亡率的预测价值。结果：运动期和恢复期QT动力学遗传度分别为10.7%和5.4%。全基因组关联研究确定了20个基因座，其中4个基因座包括与孟德尔长QT综合征有关的基因。有5个基因座与已报道的静止QT间期基因座不重叠；候选基因包括KCNQ4和KIAA1755。在来自英国生物库的357 882名无关个体中，遗传风险得分与心血管事件无关。我们也没有观察到运动和康复期间QT动态与心血管事件的相关性。在单变量COX回归分析中，恢复期QT动态增强与全因死亡率显著相关(危险比，1.09[95%可信区间，1.05-1.13]，P=2.28x10(-5))，但在调整临床危险因素后，这种相关性并不显著。结论：运动和康复期间的QT间期动态变化是可遗传的标记，但在英国生物库中并不携带临床结果的独立预后信息，这是一个基于人群的队列。它们的预后重要性可能与心血管疾病队列有关，在这些队列中，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间期基因座之间的强烈重叠提示了共同的生物学途径；然而，不重叠的基因座提示可能存在其他机制，这些机制可能是QT间期动力学的基础。
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 includedKCNQ4andKIAA1755. 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=2.28x10(-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.