Relationship between KCNQ1 (LQT1) and KCNH2 (LQT2) gene mutations and sudden death during illegal drug use
Relationship between KCNQ1 (LQT1) and KCNH2 (LQT2) gene mutations and sudden death during illegal drug use
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DOI：
10.1038/s41598-018-26723-8
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发表时间：
2018-05-31
影响因子：
4.6
通讯作者：
Iwase, Hirotaro
中科院分区：
文献类型：
--
作者：
Nagasawa, Sayaka;Saitoh, Hisako;Iwase, Hirotaro
长QT综合征（LQTS）是一种先天性遗传疾病，可导致点扭转（TdP），致命的心律失常可能由摄入心脏毒性药物引起。甲基苯丙胺（Methamphetamine， MP）和新型精神活性物质（new psychoactive substances, nps）可因QT间期延长而诱发TdP，导致猝死。因此，我们分析了lqts相关基因KCNQ1 （LQT1）和KCNH2 （LQT2）的变异，使用MP或NPS使用期间突然死亡的受试者的心脏血液和心肌组织，以研究先天性遗传异常与非法药物使用期间猝死之间的关系。我们使用来自20名受试者的样本扩增并测序了这些基因的所有外显子，其中一半在服用MP后死亡，另一半在服用nps后死亡。G643S是一种KCNQ1错义多态性，在nps（6例）的猝死中比MP（1例）和健康日本人的猝死中更常见（P = 0.001）。值得注意的是，3例G643S携带者中有2例检测到合成卡西酮。先前的功能分析表明，KCNQ1钾通道基因的G643S多态性导致轻度I-Ks通道功能障碍。我们的数据表明，使用nps，特别是合成卡西酮，与携带KCNQ1 G643S的受试者发生严重心律失常和猝死的风险升高有关。
Long QT syndrome (LQTS), a congenital genetic disorder, can cause torsades de pointes (TdP), and lethal cardiac arrhythmia may result from ingestion of cardiotoxic drugs. Methamphetamine (MP) and new psychoactive substances (NPSs) can trigger TdP due to QT prolongation, leading to sudden death. We therefore analysed variations in the LQTS-associated genes KCNQ1 (LQT1) and KCNH2 (LQT2) using cardiac blood and myocardial tissue from subjects having died suddenly during MP or NPS use to investigate the relationship between congenital genetic abnormalities and sudden death during illegal drug use. We amplified and sequenced all exons of these genes using samples from 20 subjects, half of whom had died taking MP and half after using NPSs. G643S, a KCNQ1 missense polymorphism, was significantly more common among sudden deaths involving NPSs (6 subjects) than those involving MP (1 subject) and healthy Japanese subjects (P = 0.001). Notably, synthetic cathinones were detected in 2 of 3 cases involving G643S carriers. Previous functional analyses have indicated that the G643S polymorphism in the KCNQ1 potassium channel gene causes mild I-Ks channel dysfunction. Our data suggest that use of NPSs, particularly synthetic cathinones, is associated with elevated risk of serious cardiac arrhythmia and sudden death for subjects carrying KCNQ1 G643S.