Common Variation in the NOS1AP Gene Is Associated With Drug-Induced QT Prolongation and Ventricular Arrhythmia

Study Questions:

What is the association between NOS1AP gene variation and drug-induced long QT syndrome (LQTS)?


A genetic association study using 167 single nucleotide polymorphisms (SNPs) spanning the NOS1AP gene in 58 patients experiencing drug-induced LQTS (dLQTS) and 87 controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study was performed.


The rs10800397 SNP was significantly associated with dLQTS (odds ratio [OR], 3.3; p = 3.7 x 10 –4). The associations were more pronounced in the subgroup of amiodarone users, in which three SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR, 5.5; p = 3.0 x 10–4). This SNP was analyzed in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (OR, 2.81, p = 2.4 x 10–4). The corrected QT interval among 74 control subjects from this data set 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 British Genetics of Hypertension Study cohort (increase in corrected QT interval per C allele of SNP rs12734991: 9.1 ± 3.2 ms, p = 1.7 x 10–4).


These results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS.


Genetic-based risk stratification for drug-induced proarrhythmia could be very useful in the management of patients with dysrhythmias. Previous genome-wide association studies have found associations between the QT interval and NOS1AP gene variation. This study demonstrates that NOS1AP gene variation is also associated with drug-induced LQTS, suggesting subjects at risk may lack ‘repolarization reserve.’ Although the mechanism underlying this association remains to be elucidated, these findings may prove useful in guiding antiarrhythmic drug therapy.

Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias

Keywords: Polymorphism, Single Nucleotide, Biological Markers, Genetic Association Studies, Long QT Syndrome

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