Journal Article

Genome Wide Analysis of Drug-Induced Torsades de Pointes: Lack of Common Variants with Large Effect Sizes

Kannankeril, Prince J., George, Alfred L., Steinbeck, Gerhard, Jamshidi, Yalda, Wilde, Arthur A. M., Bastiaenen, Rachel, Norris, Kris, Bezzina, Connie R., Camm, A. John, Tatonetti, Nicholas P., Schott, Jean-Jacques, Myerburg, Robert J., Roden, Dan M., Guicheney, Pascale, Dalageorgou, Chrysoula, Kubo, Michiaki, Nakamura, Yusuke, Bevan, Steve, Shen, Yufeng, Crawford, Dana C., Shakir, Saad, Schulze-Bahr, Eric, Behr, Elijah R., Zumhagen, Sven, Marshall, Vanessa, Jeffery, Steve, Floratos, Aris, Nicoletti, Paola, Ritchie, Marylyn D., Altman, Russ B., Bishopric, Nanette H., Sinner, Moritz F., Tanaka, Toshihiro, Kääb, Stefan

2013

Overview

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adolescent / Adult / Aged / Aged, 80 and over / Alleles / Analysis / Anti-Arrhythmia Agents - adverse effects / Antiarrhythmia agents / Arrhythmia / Arrhythmias, Cardiac - drug therapy / Arrhythmias, Cardiac - ethnology / Arrhythmias, Cardiac - genetics / Arrhythmias, Cardiac - physiopathology / Association analysis / Biophysics / Cardiac arrhythmia / Cardiology / Child / Confidence intervals / Departments / Drugs / EKG / Electrocardiography / Female / Gene Frequency / Genes / Genetic diversity / Genetic Loci / Genetic Predisposition to Disease / Genetic variance / Genetics / Genome, Human / Genome-Wide Association Study / Genomes / Genomics / Haplotypes / Health risk assessment / Heart failure / Hospitals / Humans / Informatics / Long QT syndrome / Male / Medicine / Middle Aged / Mutation / Odds Ratio / Pediatrics / Pharmacology / Physicians / Physiology / Polymorphism / Polymorphism, Single Nucleotide / Population structure / Principal components analysis / Product safety / Prolongation / Regression analysis / Risk analysis / Risk factors / Safety research / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Statistical analysis / Tachycardia / Torsades de pointes / Torsades de Pointes - chemically induced / Torsades de Pointes - ethnology / Torsades de Pointes - genetics / Torsades de Pointes - physiopathology / Ventricle / White People