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. 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.
Cardiovascular Sciences and Genetics Research Centers, St George's University of London, London, United Kingdom.
Elijah R
ER
Behr
Marylyn D
MD
Ritchie
Toshihiro
T
Tanaka
Stefan
S
Kääb
Dana C
DC
Crawford
Paola
P
Nicoletti
Aris
A
Floratos
Moritz F
MF
Sinner
Prince J
PJ
Kannankeril
Arthur A M
AA
Wilde
Connie R
CR
Bezzina
Eric
E
Schulze-Bahr
Sven
S
Zumhagen
Pascale
P
Guicheney
Nanette H
NH
Bishopric
Vanessa
V
Marshall
Saad
S
Shakir
Chrysoula
C
Dalageorgou
Steve
S
Bevan
Yalda
Y
Jamshidi
Rachel
R
Bastiaenen
Robert J
RJ
Myerburg
Jean-Jacques
JJ
Schott
A John
AJ
Camm
Gerhard
G
Steinbeck
Kris
K
Norris
Russ B
RB
Altman
Nicholas P
NP
Tatonetti
Steve
S
Jeffery
Michiaki
M
Kubo
Yusuke
Y
Nakamura
Yufeng
Y
Shen
Alfred L
AL
George
Dan M
DM
Roden
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics / Q000503:physiopathology; D002648:Child; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016171:Torsades de Pointes / Q000139:chemically induced / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D044465:White People
D000889:Anti-Arrhythmia Agents