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

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• 作者：Yalda Jamshidi ; Ilja M. Nolte ; Chrysoula Dalageorgou ; Dongling Zheng ; Toby Johnson ; Rachel Bastiaenen ; Suzanne Ruddy ; Daniel Talbott ; Kris J. Norris ; Harold Snieder ; Alfred L. George ; Vanessa Marshall ; Saad Shakir ; Prince J. Kannankeril ; Patricia B. Munroe ; A. John Camm ; Steve Jeffery ; Dan M. Roden ; Elijah R. Behr
• 关键词：cardiac arrhythmias ; drug ; genetics ; NOS1AP ; risk stratification ; single nucleotide polymorphisms
• 刊名：Journal of the American College of Cardiology
• 出版年：2012
• 出版时间：28 August, 2012
• 年：2012
• 卷：60
• 期：9
• 页码：841-850
• 全文大小：887 K

文摘

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Objectives

This study sought to determine whether variations in m>NOS1APm> 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. m>NOS1APm> 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 m>NOS1APm> 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 ¡Á 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 ¡Á 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 ¡Á 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 ¡À 3.2 ms, p = 1.7 ¡Á 10^-4).

Conclusions

These results provide the first demonstration that common variations in the m>NOS1APm> gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the m>NOS1APm> gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.