TY - JOUR
T1 - Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome
AU - Weeke, Peter
AU - Mosley, Jonathan D.
AU - Hanna, David
AU - Delaney, Jessica T.
AU - Shaffer, Christian
AU - Wells, Quinn S.
AU - Van Driest, Sara
AU - Karnes, Jason H.
AU - Ingram, Christie
AU - Guo, Yan
AU - Shyr, Yu
AU - Norris, Kris
AU - Kannankeril, Prince J.
AU - Ramirez, Andrea H.
AU - Smith, Joshua D.
AU - Mardis, Elaine R.
AU - Nickerson, Deborah
AU - George, Alfred L.
AU - Roden, Dan M.
N1 - Funding Information:
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).
PY - 2014/4/15
Y1 - 2014/4/15
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jacc.2014.01.031
DO - 10.1016/j.jacc.2014.01.031
M3 - Article
C2 - 24561134
AN - SCOPUS:84897985012
SN - 0735-1097
VL - 63
SP - 1430
EP - 1437
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 14
ER -