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

• Published in: Journal of the American College of Cardiology Vol. 63; no. 14; pp. 1430 - 1437
• Main Authors: Weeke, Peter, Mosley, Jonathan D., Hanna, David, Delaney, Jessica T., Shaffer, Christian, Wells, Quinn S., Van Driest, Sara, Karnes, Jason H., Ingram, Christie, Guo, Yan, Shyr, Yu, Norris, Kris, Kannankeril, Prince J., Ramirez, Andrea H., Smith, Joshua D., Mardis, Elaine R., Nickerson, Deborah, George, Alfred L., Roden, Dan M.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.04.2014; Elsevier; Elsevier Limited
• Subjects: Adult; adverse drug event; Aged; Alleles; Amino acids; Biological and medical sciences; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Cardiovascular; Case-Control Studies; Drug-Related Side Effects and Adverse Reactions - genetics; Electrocardiography; exome; Exome - genetics; Female; Genealogy; Genes; Genetic Predisposition to Disease - epidemiology; Genetic Variation; genetics; Genomes; Genotype; Heart; Humans; Incidence; KCNQ1 Potassium Channel - genetics; long QT interval syndrome; Long QT Syndrome - chemically induced; Long QT Syndrome - epidemiology; Long QT Syndrome - genetics; Male; Medical sciences; Middle Aged; Mutation; Population; Potassium Channels - genetics; Potassium Channels, Voltage-Gated - genetics; Predictive Value of Tests; Principal components analysis; Reference Values; Risk Assessment; Sequence Analysis, Protein; torsade des pointes; Torsades de Pointes - chemically induced; Torsades de Pointes - epidemiology; Torsades de Pointes - genetics; QTc; TdP; AAC; ESP; WES; LQTS; long QT interval syndrome; torsade des pointes; SKAT; ADR; IKs; cLQTS; IKr; exome; genetics; MAF; SNP; adverse drug event; diLQTS; EA; VT; adverse drug event(s); sequence kernel association test; single nucleotide polymorphism; congenital long QT interval syndrome; cardiac slow delayed potassium rectifier current; I Ks; I Kr; European-American; corrected QT interval; torsades de pointes; amino acid coding; whole exome sequencing; minor allele frequency; cardiac delayed rectifier potassium current; variable threshold; drug-induced long QT interval syndrome; Exome Sequencing Project; Drug; Arrhythmia; Nucleotide sequence; Prolonged QT interval; Cardiovascular disease; Risk; Ionic channel; Inorganic element; Conduction disorder; Variant; Heart block; Heart disease; Risk factor; Circulatory system; Cardiology; Potassium; Sequencing; Interval
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2014.01.031

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. 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. 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. 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). 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.