Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.
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. A...
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2013-01-01
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| Online Access: | https://doi.org/10.1371/journal.pone.0078511 |
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| author | 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 Dan M Roden |
| author_facet | 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 Dan M Roden |
| author_sort | Elijah R Behr |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-3e85dcfe215d421eb42dff29deda650d |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-3e85dcfe215d421eb42dff29deda650d2025-08-20T03:46:23ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e7851110.1371/journal.pone.0078511Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.Elijah R BehrMarylyn D RitchieToshihiro TanakaStefan KääbDana C CrawfordPaola NicolettiAris FloratosMoritz F SinnerPrince J KannankerilArthur A M WildeConnie R BezzinaEric Schulze-BahrSven ZumhagenPascale GuicheneyNanette H BishopricVanessa MarshallSaad ShakirChrysoula DalageorgouSteve BevanYalda JamshidiRachel BastiaenenRobert J MyerburgJean-Jacques SchottA John CammGerhard SteinbeckKris NorrisRuss B AltmanNicholas P TatonettiSteve JefferyMichiaki KuboYusuke NakamuraYufeng ShenAlfred L GeorgeDan M RodenMarked 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.https://doi.org/10.1371/journal.pone.0078511 |
| spellingShingle | 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 Dan M Roden Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes. PLoS ONE |
| title | Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes. |
| title_full | Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes. |
| title_fullStr | Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes. |
| title_full_unstemmed | Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes. |
| title_short | Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes. |
| title_sort | genome wide analysis of drug induced torsades de pointes lack of common variants with large effect sizes |
| url | https://doi.org/10.1371/journal.pone.0078511 |
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