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.
| Original language | English (US) |
|---|---|
| Article number | e78511 |
| Journal | PloS one |
| Volume | 8 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 6 2013 |
Funding
The authors have the following interests. AAMW is a member of the scientific advisory board of Sorin. RJM reports consultancy for Sanofi-Aventis, GSK, and Boston Scientific. He reports various expert testimonies not related to the present study. He was paid for lectures by Sanofi-Aventis and Boston Scientific. Travel and accommodations have been paid by Sanofi-Aventis. He is chair of DSMB of a multicenter study co-supported by the National Heart, Lung, and Blood Institute, and Medtronic, GE, and Zoll. AJC has acted as a consultant for Sanofi, Servier, Daiichi, Boehringer Ingelheim, Bayer, Novartis, Gilead and Menarini. He is a member of DSMB for studies funded by Servier, Novartis, BMs and Pfizer. ALG reports additional funding to his institution by Gilead Sciences to study proprietary compounds, but unrelated to the present study. Together with DMR he holds U.S. Letters Patent No. 6,458,542, issued October 1, 2002 for "Method of Screening for Susceptibility to Drug-Induced Cardiac Arrhythmia". For this particular study the DARE samples were genotyped at Gene Expression Ltd. Further support was provided by a collaboration with the International Serious Adverse Events Consortium, whose membership currently includes Abbott, Amgen, Astra-Zeneca, Cerner, Daiichi-Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda, and the Welcome Trust. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
ASJC Scopus subject areas
- General