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

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

PLOS ONE, 2013, vol. 8, issue 11, 1-9

Abstract: 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.

Date: 2013
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0078511

DOI: 10.1371/journal.pone.0078511

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