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

Abstract

BACKGROUND Use of anti-arrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. Recent studies have demonstrated a role for NOS1AP gene variants in modulating QT interval in healthy subjects and modification of the severity of presentation and the risk of arrhythmias in LQTS. METHODS We carried out an association study using 167 SNPs spanning the NOS1AP gene in 58 Caucasian patients experiencing dLQTS and 87 Caucasian controls from the DARE Study. RESULTS Association analysis identified one polymorphism significantly associated with dLQTS (rs10800397: p=3.7×10−4; OR=3.3, 99.95% CI=1.0–10.8). The associations were more pronounced in the subgroup of amiodarone users, in which three SNPs including rs10800397 were significantly associated (most significant SNP rs10919035: p=3.0×10−4; OR=5.5, 99.95% CI=1.1–27.9). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone-dLQTS cases versus 173 controls (meta-analysis of both studies: OR=2.81; p=2.4×10−4; 95% CI=1.62–4.89). Analysis of QTc among 74 controls 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 controls from the BRIGHT cohort (top SNP DARE rs12734991 in meta-analysis: mean [SD] increase in QTc interval per C allele=9.1 [3.2]ms; p=1.7×10−4). CONCLUSIONS Our results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. We suggest that common variation in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.

NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling

“…In summary, we have shown that NOS1AP is a highly spliced protein, with the different isoforms having differential tissue expression and subcellular localizations and forming different signaling complexes. Given that NOS1AP has been implicated in a number of disorders, including bipolar disorder (23,37), schizophrenia (38), QT syndrome (14,39,40), anxiety (13), and post-C D…”

Pharmacokinetic and pharmacodynamic profile of dronedarone, a new antiarrhythmic agent for the treatment of atrial fibrillation

“…It should be noted that recent works have hypothesized that the response to antiarrhytmic drug therapy is influenced by a common polymorphism on chromosome 4q25 near PITX2 gene [37] and that the risk of proarrhythmic effect is modulated by common variants in nitric oxide synthase 1 adaptor protein [38], thus explaining the patient-to-patient variations in response and proarrhtmic effect.…”

Unveiling Specific Triggers and Precipitating Factors for Fatal Cardiac Events in Inherited Arrhythmia Syndromes

“…44, 46 Common variants of NOS1AP have been reported to be associated with a significant increase in the risk of dLQTS. 47 Also, common variants in drug metabolism pathways may also predispose to dLQTS in a drug-specific fashion.…”