1. Genome Wide Analysis of Drug-Induced Torsades de Pointes: Lack of Common Variants with Large Effect Sizes.
- Author
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Behr, Elijah R., Ritchie, Marylyn D., Tanaka, Toshihiro, Kääb, Stefan, Crawford, Dana C., Nicoletti, Paola, Floratos, Aris, Sinner, Moritz F., Kannankeril, Prince J., Wilde, Arthur A. M., Bezzina, Connie R., Schulze-Bahr, Eric, Zumhagen, Sven, Guicheney, Pascale, Bishopric, Nanette H., Marshall, Vanessa, Shakir, Saad, Dalageorgou, Chrysoula, Bevan, Steve, and Jamshidi, Yalda
- Subjects
ELECTROCARDIOGRAPHY ,VENTRICULAR tachycardia ,ADVERSE health care events ,PHARMACODYNAMICS ,SINGLE nucleotide polymorphisms ,LOGISTIC regression analysis ,DIAGNOSIS ,THERAPEUTICS ,DISEASE risk factors - 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. [ABSTRACT FROM AUTHOR]- Published
- 2013
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