Author + information
- Received October 9, 2013
- Revision received December 9, 2013
- Accepted January 7, 2014
- Published online April 15, 2014.
- Peter Weeke, MD∗,†,
- Jonathan D. Mosley, MD, PhD∗,
- David Hanna, BS‡,
- Jessica T. Delaney, MD∗,
- Christian Shaffer, BS∗,
- Quinn S. Wells, MD∗,
- Sara Van Driest, MD, PhD§,
- Jason H. Karnes, PharmD, PhD∗,
- Christie Ingram, BS∗,
- Yan Guo, PhD||,
- Yu Shyr, PhD||,
- Kris Norris, RN∗,
- Prince J. Kannankeril, MD§,
- Andrea H. Ramirez, MD∗,
- Joshua D. Smith, BS‡,
- Elaine R. Mardis, PhD¶,
- Deborah Nickerson, PhD‡,
- Alfred L. George Jr., MD# and
- Dan M. Roden, MD#∗ ()
- ∗Department of Medicine, Vanderbilt University, Nashville, Tennessee
- †Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark
- ‡Department of Genome Sciences, University of Washington, Seattle, Washington
- §Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
- ||Vanderbilt Technologies for Advanced Genomics Analysis and Research Design, Nashville, Tennessee
- ¶The Genome Institute, Washington University, St. Louis, Missouri
- #Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee
- ↵∗Reprint requests and correspondence
: Dr. Dan M. Roden, Vanderbilt University School of Medicine, 1285 Medical Research Building IV, Nashville, Tennessee 37232.
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.
This study was supported by the Pharmacogenomics of Arrhythmia Therapy site and the Deep Sequencing Resources of the Pharmacogenetics Research Network (grants U19HL065962, U19HL069757, and U01 GM97119), by a grant from the Fondation Leducq (Trans-Atlantic Network of Excellence “Alliance Against Sudden Cardiac Death,” 05 CVD 01), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), NIH/NCRR (G20 RR030956), and a training grant in Clinical Pharmacology GM07569. Dr. Weeke was funded by an unrestricted research grant from the Tryg Foundation (J.nr. 7343-09, TrygFonden, Denmark).
Drs. Roden and George hold U.S. Letters Patent No. 6,458,542, issued October 1, 2002, for the “Method of Screening for Susceptibility to Drug-Induced Cardiac Arrhythmia,” focusing on the D85N variant; both have received past royalties. Dr. George has received additional funding to his institution by Gilead Sciences to study proprietary compounds, but unrelated to the present study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 9, 2013.
- Revision received December 9, 2013.
- Accepted January 7, 2014.
- American College of Cardiology Foundation