Clinical Research
Heart Rhythm Disorders
Common Variation in the NOS1AP Gene Is Associated With Drug-Induced QT Prolongation and Ventricular Arrhythmia

https://doi.org/10.1016/j.jacc.2012.03.031Get rights and content
Under an Elsevier user license
open archive

Objectives

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.

Key Words

cardiac arrhythmias
drug
genetics
NOS1AP
risk stratification
single nucleotide polymorphisms

Abbreviations and Acronyms

CEU
western and northern European ancestry
CI
confidence interval
DNA
deoxyribonucleic acid
ECG
electrocardiogram
IRB
Institutional Review Board
LD
linkage disequilibrium
LQTS
long QT syndrome
nNOS
neuronal nitric oxide synthase
NOS1AP
nitric oxide synthase 1 adaptor protein
OR
odds ratio
SNP
single nucleotide polymorphism
TdP
torsades de pointes

Cited by (0)

The DARE study was funded by the British Heart Foundation (BHF), Project Grant No. 06/094 (to Dr. Jamshidi) and Special Program Grant No. SP/02/001 (to Dr. Camm). The Vanderbilt study was supported by Grant No. U01/U19 HL65962, the Pharmacogenomics of Arrhythmia Therapy site of the Pharmacogenomics Research Network, and by a grant from the Fondation Leducq (Trans-Atlantic Network of Excellence “Alliance Against Sudden Cardiac Death,” 05 CVD 01). The BRIGHT study was supported by the Medical Research Council of Great Britain (Grant No. G9521010D) and by BHF Grant No. PG/02/128. Genotyping for the Human_CVD BeadChip was supported by BHF Grant No. PG/07/131/24254 (to Dr. Munroe). This work forms part of the research themes contributing to the translational research portfolio for Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute for Health Research. Dr. Johnson has received research funding from Wellcome Trust (Grant No. 093078/Z/10/Z); and is an employee of GlaxoSmithKline. Dr. George has received research grants from Gilead Sciences and Allergan Inc. Dr. Camm is an advisor and speaker for Boehringer Ingelheim, Bayer, Daiichi, Pfizer, Bristol-Myers Squibb, Sanofi, Servier, Xention, Medtronic, Boston Scientific, Gilead, and Menarini; is a data and safety monitoring board member for Cameron Health, Biotronik, Novartis, Astellas, Forest Labs, Servier, and Bioctcontrol; is an events committee member for Novartis; has research contracts with Sanofi, Boehringer Ingelheim, Daiichi, Menarini, Richmond Pharmacology; and is a consultant for Cardialysis. Dr. Roden has received consulting fees from Astellas, Sanofi, and Warner-Chicott. Dr. Behr has received research funding from Biotronik, the International Serious Adverse Events Consortium, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Jamshidi and Nolte contributed equally to this paper.