Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela (A Coruña), Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.
Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela (A Coruña), Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.
Forensic Sci Int Genet. 2019 Sep;42:203-212. doi: 10.1016/j.fsigen.2019.07.010. Epub 2019 Jul 18.
Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity.
药物性心律失常是一种药物不良反应，可能具有致命性，因为它主要与药物引起的 QT 间期延长有关，而 QT 间期延长是尖端扭转型室性心动过速和心脏性猝死（SCD）的已知危险因素。已经描述了与这些药物引起的事件相关的几个危险因素，例如先前存在的心脏病和遗传变异。我们的目的是研究 32 名疑似药物引起心律失常和突发性不明原因死亡患者的药效学和药代动力学途径中的遗传易感性。通过大规模平行测序分析与 SCD 风险增加相关的 96 个基因，研究药效学途径中的遗传成分。通过研究编码细胞色素 P450 酶的基因，使用中通量基因分型研究药代动力学介导的遗传易感性。药效学分析显示 28 名患者中有 3 种可能的致病性变异和 45 种意义不确定的变异，其中一些先前与轻度或迟发性心肌病有关。这些结果表明，除了与通道病相关的基因外，心肌病基因中的遗传变异可能与药物引起的心脏毒性有关，并有助于心律失常表型。药代动力学分析显示 3 名患者可能对他们接受的药物的代谢发生改变，涉及 CYP2C19 和/或 CYP2D6，可能有助于心律失常表型。研究药效学和药代动力学途径中的遗传变异可能是理解临床实践和法医领域药物引起的事件的多因素机制的有用策略。然而，有必要全面研究和评估遗传易感性对药物引起的心脏毒性的贡献。
