title: Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Weeke
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: David
authors.initials: D
authors.lastname: Hanna
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Delaney
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Christian
authors.initials: C
authors.lastname: Shaffer
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Quinn S
authors.initials: QS
authors.lastname: Wells
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Sara
authors.initials: S
authors.lastname: Van Driest
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Karnes
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Christie
authors.initials: C
authors.lastname: Ingram
authors.affiliation: Vanderbilt Technologies for Advanced Genomics Analysis and Research Design, Nashville, Tennessee.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Vanderbilt Technologies for Advanced Genomics Analysis and Research Design, Nashville, Tennessee.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Kris
authors.initials: K
authors.lastname: Norris
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Prince J
authors.initials: PJ
authors.lastname: Kannankeril
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Ramirez
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: The Genome Institute, Washington University, St. Louis, Missouri.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Deborah
authors.initials: D
authors.lastname: Nickerson
authors.affiliation: Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.affiliation: Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee. Electronic address: dan.roden@vanderbilt.edu.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015994:Incidence; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D011237:Predictive Value of Tests; D012016:Reference Values; D018570:Risk Assessment; D020539:Sequence Analysis, Protein; D016171:Torsades de Pointes / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*
chemical_list: D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated
keywords: adverse drug event; exome; genetics; long QT interval syndrome; torsade des pointes