Dan Roden
Faculty Member
Last active: 2/8/2016

Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome.

Weeke P, Mosley JD, Hanna D, Delaney JT, Shaffer C, Wells QS, Van Driest S, Karnes JH, Ingram C, Guo Y, Shyr Y, Norris K, Kannankeril PJ, Ramirez AH, Smith JD, Mardis ER, Nickerson D, George AL, Roden DM
J Am Coll Cardiol. 2014 63 (14): 1430-7

PMID: 24561134 · PMCID: PMC4018823 · DOI:10.1016/j.jacc.2014.01.031

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 variable threshold compared with drug-exposed controls (p < 0.001). Of these, we replicated the diLQTS associations for KCNE1 and ACN9 using 515 Exome Sequencing Project control subjects (p < 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 = 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.

Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

MeSH Terms (23)

Adult Aged Alleles Case-Control Studies Drug-Related Side Effects and Adverse Reactions Exome Female Genetic Predisposition to Disease Genetic Variation Genotype Humans Incidence KCNQ1 Potassium Channel Long QT Syndrome Male Middle Aged Potassium Channels Potassium Channels, Voltage-Gated Predictive Value of Tests Reference Values Risk Assessment Sequence Analysis, Protein Torsades de Pointes

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