Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia.
OBJECTIVE
This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS).


BACKGROUND
Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in modulating QT intervals in healthy subjects and severity of presentation in LQTS.


METHODS
This study carried out an association study using 167 single nucleotide polymorphisms (SNP) spanning the NOS1AP gene in 58 Caucasian patients experiencing drug-induced LQTS (dLQTS) and 87 Caucasian controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study.


RESULTS
The rs10800397 SNP was significantly associated with dLQTS (odds ratio [OR]: 3.3, 99.95% confidence interval [CI]: 1.0 to 10.8, p = 3.7 × 10(-4)). The associations were more pronounced in the subgroup of amiodarone users, in which 3 SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR: 5.5, 99.95% CI: 1.1 to 27.9, p = 3.0 × 10(-4)). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (meta-analysis of both studies: OR: 2.81, 99.95% CI: 1.62 to 4.89, p = 2.4 × 10(-4)). Analysis of corrected QT interval among 74 control subjects from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 control subjects from the BRIGHT (British Genetics of Hypertension Study) cohort (top SNP from DARE: rs12734991 in meta-analysis: increase in corrected QT interval per C allele: 9.1 ± 3.2 ms, p = 1.7 × 10(-4)).


CONCLUSIONS
These results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.
St. George's University of London, London, UK. y.jamshidi@sgul.ac.uk
Yalda
Y
Jamshidi
Ilja M
IM
Nolte
Chrysoula
C
Dalageorgou
Dongling
D
Zheng
Toby
T
Johnson
Rachel
R
Bastiaenen
Suzanne
S
Ruddy
Daniel
D
Talbott
Kris J
KJ
Norris
Harold
H
Snieder
Alfred L
AL
George
Vanessa
V
Marshall
Saad
S
Shakir
Prince J
PJ
Kannankeril
Patricia B
PB
Munroe
A John
AJ
Camm
Steve
S
Jeffery
Dan M
DM
Roden
Elijah R
ER
Behr
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone / Q000009:adverse effects*; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000235:genetics; D014693:Ventricular Fibrillation / Q000139:chemically induced* / Q000235:genetics; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D000889:Anti-Arrhythmia Agents; C488081:NOS1AP protein, human; D000638:Amiodarone