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

PLoS One. 2013 Nov 6;8(11):e78511. doi: 10.1371/journal.pone.0078511. eCollection 2013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Anti-Arrhythmia Agents / adverse effects*
  • Arrhythmias, Cardiac / drug therapy
  • Arrhythmias, Cardiac / ethnology
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / 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
  • Torsades de Pointes / ethnology
  • Torsades de Pointes / genetics*
  • Torsades de Pointes / physiopathology
  • White People

Substances

  • Anti-Arrhythmia Agents