Relationship between KCNQ1 (LQT1) and KCNH2 (LQT2) gene mutations and sudden death during illegal drug use

Sayaka Nagasawa,Hisako Saitoh,Hirotaro Iwase,Hiroko Abe,Shiori Kasahara,Fumiko Chiba,Daisuke Yajima,Suguru Torimitsu

doi:10.1038/s41598-018-26723-8

Abstract

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 IKs 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.

Highlights

Methamphetamine (MP) has a high potential for abuse and MP addiction has become a serious social problem worldwide[1,2]
Post-mortem genetic analysis may provide insight into the pathogenesis of sudden death during illegal drug use. Considering this and the abovementioned findings, we focused on 2 genes (KCNQ1 and KCNH2) associated with potassium channel abnormalities, performing sequence analysis using cardiac blood and myocardial tissue from subjects having died suddenly during MP or new psychoactive substances (NPSs) use to investigate the relationship between congenital abnormalities in these genes and sudden death related to illegal drugs with QT prolonging effects
We screened for mutations in KCNQ1 and KCNH2 in 3 groups: 10 cases of sudden death involving MP use, 10 cases involving NPS use, and a control group comprising 100 Japanese individuals without Long QT syndrome (LQTS)

Summary

Introduction

Methamphetamine (MP) has a high potential for abuse and MP addiction has become a serious social problem worldwide[1,2]. In 2014, Kamei et al reported that mutations of KCNQ1 and KCNH2 are significantly more common among patients having died suddenly during therapy with antipsychotic drugs with QT prolonging action, and suggested that these genes are involved in sudden death associated with antipsychotic drug use[19]. Post-mortem genetic analysis may provide insight into the pathogenesis of sudden death during illegal drug use Considering this and the abovementioned findings, we focused on 2 genes (KCNQ1 and KCNH2) associated with potassium channel abnormalities, performing sequence analysis using cardiac blood and myocardial tissue from subjects having died suddenly during MP or NPS use to investigate the relationship between congenital abnormalities in these genes and sudden death related to illegal drugs with QT prolonging effects

Methods

Results

Discussion

Conclusion