Biological Sciences Division
Published November 6, 2013 | Version v1
Journal article Open

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

Creators

  • 1. St. George's University of London
  • 2. Vanderbilt University
  • 3. Tokyo Medical and Dental University
  • 4. Ludwig-Maximilians-University Munich
  • 5. Columbia University
  • 6. University of Amsterdam
  • 7. University Hospital Münster
  • 8. University Pierre et Marie Curie
  • 9. University of Miami
  • 10. Drug Safety Research Unit
  • 11. University of Chicago

Description

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.

Data availability

Portions of the Leducq dataset have been deposited at dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000331.v1.p1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Additional details

Identifiers

DOI
10.1371/journal.pone.0078511
Other
oai:uchicago.tind.io:8216

Funding

National Institutes of Health
U01HL65962
PharmacoGenetics (China)
Fondation Leducq
Trans-Atlantic Network of Excellence “Alliance Against Sudden Cardiac Death”
Ministry of Education, Culture, Sports, Science and Technology
BioBank Japan Project
British Heart Foundation
SP/02/001

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Medicine