ArticleJournal of the American College of Cardiology2014
Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome.
Article in Journal of the American College of Cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 2 of them syntheses that pooled it.
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Who cites it
37 citing papers in PubMed, 2 syntheses or guidelines pooled it, 75 citations in OpenAlex.
- Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.Nature genetics · 2017Pooled it
- Pharmacogenomic markers associated with drug-induced QT prolongation: a systematic review.PharmacogenomicsPooled it
- An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.Circulation · 2020Trial
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.Cardiovascular research · 2024Article
- Genetic risk factors for drug-induced long QT syndrome: findings from a large real-world case-control study.Pharmacogenomics · 2024Observational
- The genetics of drug-induced QT prolongation: evaluating the evidence for pharmacodynamic variants.Pharmacogenomics · 2022Review
- Common Ancestry-Specific Ion Channel Variants Predispose to Drug-Induced Arrhythmias.Circulation · 2022Article
- The role of pharmacogenomics in contemporary cardiovascular therapy: a position statement from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.European heart journal. Cardiovascular pharmacotherapy · 2022Article
- Sex-specific IHeart rhythm · 2021Article
- The Prevalence, Risk Factors and Clinical Correlates of QTc Prolongation in Chinese Hospitalized Patients With Chronic Schizophrenia.Frontiers in psychiatry · 2021Article
- A current understanding of drug-induced QT prolongation and its implications for anticancer therapy.Cardiovascular research · 2019Review
- Time Series Gene Expression Profiling and Temporal Regulatory Pathway Analysis of Angiotensin II Induced Atrial Fibrillation in Mice.Frontiers in physiology · 2019Article
- Identification of a Genomic Region betweenClinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant.Heart rhythm · 2018Article
- Cardiovascular safety of prokinetic agents: A focus on drug-induced arrhythmias.Neurogastroenterology and motility · 2018Review
- Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.Circulation · 2018Review
- A Heart for Diversity: Simulating Variability in Cardiac Arrhythmia Research.Frontiers in physiology · 2018Review
- Precision medicine and pharmacogenetics: what does oncology have that addiction medicine does not?Addiction (Abingdon, England) · 2017Review
- Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.Circulation · 2017Article
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Authors and funding
19 authors at 5 institutions in 2 countries.
Funding
Abstract
objectivesThe 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.
backgrounddiLQTS 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.
methodsWe 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.
resultsRare 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).
conclusionsBy 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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