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

ABSTRACT: This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS).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.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.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)).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.

SUBMITTER: Jamshidi Y

PROVIDER: S-EPMC3753216 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Jamshidi Yalda Y Nolte Ilja M IM Dalageorgou Chrysoula C Zheng Dongling D Johnson Toby T Bastiaenen Rachel R Ruddy Suzanne S Talbott Daniel D Norris Kris J KJ Snieder Harold H George Alfred L AL Marshall Vanessa V Shakir Saad S Kannankeril Prince J PJ Munroe Patricia B PB Camm A John AJ Jeffery Steve S Roden Dan M DM Behr Elijah R ER

Journal of the American College of Cardiology 20120606 9

<h4>Objectives</h4>This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS).<h4>Background</h4>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.<h4>Methods</h4>This study carried out an association study using 167 single nucleotide polymorphisms ( ...[more]

PMID: 22682551

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Project description:Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca(2+)-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source-sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias.Optical maps of action potentials and Ca(2+)-transients from Langendorff rabbit hearts were measured at low (150×150 ?m(2)/pixel) and high (1.5×1.5 ?m(2)/pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of IKr (the rapid component of rectifying K+ current), produced spontaneous Ca(2+)-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca(2+-)waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca(2+-)elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca(2+) (40%-60% of peak-Ca(2+)-transients), appeared first in small islands (0.5×0.5 mm(2)) that enlarged and spread throughout the epicardium. Synchronous systolic Ca(2+-)elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca(2+)-transient-durations and action potential-durations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca(2+)-dynamics (multiple chaotic Ca(2+)-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca(2+)-elevations and arrhythmias.The results indicate that systolic and diastolic Ca(2+)-elevations emanate from sarcoplasmic reticulum Ca(2+)-release and systolic Ca(2+)-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca(2+), which overcomes source-sink mismatch to trigger arrhythmias in intact hearts.

Project description:BackgroundDrug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known.MethodsWe tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration.ResultsThe genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r=0.55; 95% confidence interval, 0.09-0.81; P=0.02), 23% in response to quinidine (r=0.48; 95% confidence interval, -0.03 to 0.79; P=0.06), and 27% in response to ranolazine (r=0.52; 95% confidence interval, 0.05-0.80; P=0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2=12%, P=1×10-7).ConclusionsWe demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01873950.

Project description:BackgroundDrug-induced long-QT syndrome (diLQTS) is a major concern among patients who are hospitalized, for whom prediction models capable of identifying individualized risk could be useful to guide monitoring. We have previously demonstrated the feasibility of machine learning to predict the risk of diLQTS, in which deep learning models provided superior accuracy for risk prediction, although these models were limited by a lack of interpretability.ObjectiveIn this investigation, we sought to examine the potential trade-off between interpretability and predictive accuracy with the use of more complex models to identify patients at risk for diLQTS. We planned to compare a deep learning algorithm to predict diLQTS with a more interpretable algorithm based on cluster analysis that would allow medication- and subpopulation-specific evaluation of risk.MethodsWe examined the risk of diLQTS among 35,639 inpatients treated between 2003 and 2018 with at least 1 of 39 medications associated with risk of diLQTS and who had an electrocardiogram in the system performed within 24 hours of medication administration. Predictors included over 22,000 diagnoses and medications at the time of medication administration, with cases of diLQTS defined as a corrected QT interval over 500 milliseconds after treatment with a culprit medication. The interpretable model was developed using cluster analysis (K=4 clusters), and risk was assessed for specific medications and classes of medications. The deep learning model was created using all predictors within a 6-layer neural network, based on previously identified hyperparameters.ResultsAmong the medications, we found that class III antiarrhythmic medications were associated with increased risk across all clusters, and that in patients who are noncritically ill without cardiovascular disease, propofol was associated with increased risk, whereas ondansetron was associated with decreased risk. Compared with deep learning, the interpretable approach was less accurate (area under the receiver operating characteristic curve: 0.65 vs 0.78), with comparable calibration.ConclusionsIn summary, we found that an interpretable modeling approach was less accurate, but more clinically applicable, than deep learning for the prediction of diLQTS. Future investigations should consider this trade-off in the development of methods for clinical prediction.

Project description:Importance:Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial. Objective:To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills. Design, Setting, and Participants:A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018. Main Outcomes and Measures:Electrocardiographic changes 3 hours after sotalol administration. Results:A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P?=?.005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P?=?.005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n?=?13 of 61 [21.0%]) than those taking levonorgestrel (n?=?20 of 137 [14.6%]) or women taking no OCs (n?=?24 of 207 [11.6%]; P?=?.01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P?=?.01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P?<?.001). Conclusions and Relevance:Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.

Dataset Information

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

Publications

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

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