PDF(Pubmed)
Abstract：
Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17-1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS.
摘要：
药物诱导的QT延长（diLQTS），以及随后的尖端扭转风险，是使用许多药物的主要问题，包括非心脏疾病。遗传风险的可能性，以多基因风险评分(PGS)的形式，可以整合到diLQTS的风险预测中有很大的潜力，尽管目前尚不清楚遗传风险与临床风险因素的关系，这可能适用于临床决策。在这项研究中,我们使用电子健康记录数据,对2,500名暴露于已知QT延长药物的受试者的QT间期延长超过500ms后,在随后的ECG中检查了PGS的QT间期.我们发现病例的归一化QTPGS高于对照组（0.212±0.954vs.-0.0270±1.003,P=0.0002),与diLQTS相关的未调整比值比为1.34(95CI1.17-1.53，P<0.001)。当包括年龄和QT延长的临床预测因子时，我们发现QT间期的PGS为diLQTS提供了独立的风险预测，其中高风险诊断或与某些高风险药物的相互作用(胺碘酮，索他洛尔,和多非利特)不显著，表明遗传风险并未改变其他风险因素对diLQTS风险的影响.我们发现高风险截止(QTPGS≥高于平均值2个标准差)，但不是低风险的界限，与临床因素调整后的diLQTS风险相关，并提供了一种基于决策树框架的集成方法。总之,我们发现QT间隔的PGS是diLQTS的独立预测因子，但与现有的关于复极化储备作为增加风险的机制的理论相反，该效应独立于其他临床危险因素。需要更多的工作来进行临床决策的外部验证，以及定义增加QT间期的基因与diLQTS风险相关的机制。
