Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

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.

• Authors: 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 Jr, Dan M Roden
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e78511 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24223155 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Alleles
• Anti-Arrhythmia Agents (adverse effects)
• Arrhythmias, Cardiac (drug therapy, ethnology, genetics, physiopathology)
• Child
• Female
• Gene Frequency
• Genetic Loci
• Genetic Predisposition to Disease
• Genome, Human
• Genome-Wide Association Study
• Humans
• Male
• Middle Aged
• Odds Ratio
• Polymorphism, Single Nucleotide
• Torsades de Pointes (chemically induced, ethnology, genetics, physiopathology)
• White People