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

Peter Weeke, Jonathan D. Mosley, David Hanna, Jessica T. Delaney, Christian Shaffer, Quinn S. Wells, Sara Van Driest, Jason H. Karnes, Christie Ingram, Yan Guo, Yu Shyr, Kris Norris, Prince J. Kannankeril, Andrea H. Ramirez, Joshua D. Smith, Elaine R. Mardis, Deborah Nickerson, Alfred L. George, Dan M. Roden

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1430-1437
Number of pages8
JournalJournal of the American College of Cardiology
Volume63
Issue number14
DOIs
StatePublished - Apr 15 2014

Keywords

  • adverse drug event
  • exome
  • genetics
  • long QT interval syndrome
  • torsade des pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome'. Together they form a unique fingerprint.

  • Cite this

    Weeke, P., Mosley, J. D., Hanna, D., Delaney, J. T., Shaffer, C., Wells, Q. S., Van Driest, S., Karnes, J. H., Ingram, C., Guo, Y., Shyr, Y., Norris, K., Kannankeril, P. J., Ramirez, A. H., Smith, J. D., Mardis, E. R., Nickerson, D., George, A. L., & Roden, D. M. (2014). Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome. Journal of the American College of Cardiology, 63(14), 1430-1437. https://doi.org/10.1016/j.jacc.2014.01.031