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, Dan M. Roden

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.