Salem Joe-Elie, Germain Marine, Hulot Jean-Sébastien, Voiriot Pascal, Lebourgeois Bruno, Waldura Jean, Tregouet David-Alexandre, Charbit Beny, Funck-Brentano Christian
Sorbonne-Universités, UPMC Univ Paris 06, INSERM, UMRS-1166, Institute of Cardio metabolism and Nutrition (ICAN), Paris, France.
AP-HP, CIC-1421-Paris-Est, Pitié-Salpêtrière Hospital, Paris, France.
PLoS One. 2017 Aug 11;12(8):e0181875. doi: 10.1371/journal.pone.0181875. eCollection 2017.
Many drugs used for non-cardiovascular and cardiovascular purposes, such as sotalol, have the side effect of prolonging cardiac repolarization, which can trigger life-threatening cardiac arrhythmias by inhibiting the potassium-channel IKr (KCNH2). On the electrocardiogram (ECG), IKr inhibition induces an increase in QTc and Tpeak-Tend (TpTe) interval and a decrease of T wave maximal amplitude (TAmp). These changes vary markedly between subjects, suggesting the existence of predisposing genetic factors. 990 healthy individuals, prospectively challenged with an oral 80mg sotalol dose, were monitored for changes in ventricular repolarization on ECG between baseline and 3 hours post dosing. QTc and TpTe increased by 5.5±3.5% and 15±19.6%, respectively, and TAmp decreased by 13.2±15.5%. A principal-component analysis derived from the latter ECG changes was performed. A random subsample of 489 individuals were subjected to a genome-wide-association analysis where 8,306,856 imputed single nucleotide polymorphisms (SNPs) were tested for association with QTc, TpTe and TAmp modulations, as well their derived principal-components, to search for common genetic variants associated with sotalol-induced IKr inhibition. None of the studied SNPs reached the statistical threshold for genome-wide significance. This study supports the lack of common variants with larger effect sizes than one would expect based on previous ECG genome-wide-association studies.
ClinicalTrials.gov NCT00773201.
许多用于非心血管和心血管疾病治疗的药物，如索他洛尔，具有延长心脏复极的副作用，这可通过抑制钾通道IKr（KCNH2）引发危及生命的心律失常。在心电图（ECG）上，IKr抑制会导致QTc和T峰 - T末（TpTe）间期增加以及T波最大振幅（TAmp）降低。这些变化在个体之间差异显著，提示存在易感遗传因素。对990名健康个体进行前瞻性研究，口服80mg索他洛尔剂量，监测给药前基线和给药后3小时之间ECG上心室复极的变化。QTc和TpTe分别增加了5.5±3.5%和15±19.6%，TAmp降低了13.2±15.5%。对后一种ECG变化进行了主成分分析。对489名个体的随机子样本进行全基因组关联分析，测试8306856个推算的单核苷酸多态性（SNP）与QTc、TpTe和TAmp调节及其衍生主成分的关联，以寻找与索他洛尔诱导的IKr抑制相关的常见遗传变异。所研究的SNP均未达到全基因组显著性的统计阈值。本研究支持缺乏比基于先前ECG全基因组关联研究所预期的效应大小更大的常见变异。
ClinicalTrials.gov NCT00773201。
