Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia.

Jamshidi Y, Nolte IM, Dalageorgou C, Zheng D, Johnson T, Bastiaenen R, Ruddy S, Talbott D, Norris KJ, Snieder H, George AL, Marshall V, Shakir S, Kannankeril PJ, Munroe PB, Camm AJ, Jeffery S, Roden DM, Behr ER
J Am Coll Cardiol. 2012 60 (9): 841-50

PMID: 22682551 · PMCID: PMC3753216 · DOI:10.1016/j.jacc.2012.03.031

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.

Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

MeSH Terms (17)

Adaptor Proteins, Signal Transducing Adult Aged Aged, 80 and over Amiodarone Anti-Arrhythmia Agents Case-Control Studies Female Humans Long QT Syndrome Male Middle Aged Polymorphism, Single Nucleotide Sequence Analysis, DNA Torsades de Pointes Ventricular Fibrillation Young Adult

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