Exome Sequencing Implicates an Increased Burden of Rare Potassium Channel Variants in the Risk of Drug-Induced Long QT Interval Syndrome

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• 作者：Peter Weeke ; MD^&lowast ; ; ^&dagger ; ; Jonathan D. Mosley ; MD ; PhD^&lowast ; ; David Hanna ; BS^&Dagger ; ; Jessica T. Delaney ; MD^&lowast ; ; Christian Shaffer ; BS^&lowast ; ; Quinn S. Wells ; MD^&lowast ; ; Sara Van Driest ; MD ; PhD^§ ; ; Jason H. Karnes ; PharmD ; PhD^&lowast ; ; Christie Ingram ; BS^&lowast ; ; Yan Guo ; PhD^|| ; Yu Shyr ; PhD^|| ; Kris Norris ; RN^&lowast ; ; Prince J. Kannankeril ; MD^§ ; ; Andrea H. Ramirez ; MD^&lowast ; ; Joshua D. Smith ; BS^&Dagger ; ; Elaine R. Mardis ; PhD^¶ ; ; Deborah Nickerson ; PhD^&Dagger ; ; Alfred L. George Jr. ; MD^# ; Dan M. Roden ; MD^# ; ^{dan.roden@vanderbilt.edu" class="auth_mail}
• 关键词：adverse drug event ; exome ; genetics ; long QT interval syndrome ; torsade des pointes
• 刊名：Journal of the American College of Cardiology
• 出版年：15 April, 2014
• 年：2014
• 卷：63
• 期：14
• 页码：1430-1437
• 全文大小：245 K

文摘

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Objectives

The aim of this study was to test the hypothesis that rare variants are associated with drug-induced long QT interval syndrome (diLQTS) and torsades de pointes.

Background

diLQTS is associated with the potentially fatal arrhythmia torsades de pointes. The contribution of rare genetic variants to the underlying genetic framework predisposing to diLQTS has not been systematically examined.

Methods

We performed whole-exome sequencing on 65 diLQTS patients and 148 drug-exposed control subjects of European descent. We used rare variant analyses (variable threshold and sequence kernel association test) and gene-set analyses to identify genes enriched with rare amino acid coding (AAC) variants associated with diLQTS. Significant associations were reanalyzed by comparing diLQTS patients with 515 ethnically matched control subjects from the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project.

Results

Rare variants in 7 genes were enriched in the diLQTS patients according to the sequence kernel association test or聽variable threshold compared with drug-exposed controls (p聽< 0.001). Of these, we replicated the diLQTS associations for KCNE1 and ACN9 using 515 Exome Sequencing Project control subjects (p聽< 0.05). A total of 37% of the diLQTS patients also had 1 or more rare AAC variants compared with 21% of control subjects (p聽= 0.009), in a pre-defined set of 7 congenital long QT interval syndrome (cLQTS) genes encoding potassium channels or channel modulators (KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, AKAP9).

Conclusions

By combining whole-exome sequencing with aggregated rare variant analyses, we implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS. Moreover, diLQTS patients were more burdened by rare AAC variants in cLQTS genes encoding potassium channel modulators, supporting the idea that multiple rare variants, notably across cLQTS genes, predispose to diLQTS.