Polymorphisms in the NOS1AP Gene Modulate QT Interval Duration and Risk of Arrhythmias in the Long QT Syndrome

Marta Tomás, Carlo Napolitano, Luciana De Giuli, Raffaella Bloise, Isaac Subirana, Alberto Malovini, Riccardo Bellazzi, Dan E. Arking, Eduardo Marban, Aravinda Chakravarti, Peter M. Spooner, Silvia G. Priori

Research output: Contribution to journalArticle

Abstract

Objectives: We investigated the role of nitric oxide 1 adaptor protein (NOS1AP) as a genetic modifier of long QT syndrome (LQTS). Background: LQTS risk stratification is complicated by the phenotype variability that limits prediction of life-threatening arrhythmic events based on available metrics. Thus, the identification of new markers is desirable. Recent studies have shown that NOS1AP variations in the gene modulate QT interval in healthy and 1 LQTS kindred, and occurrence of cardiac events in healthy subjects. Methods: The study included 901 patients enrolled in a prospective LQTS registry. Three NOS1AP marker SNPs (rs4657139, rs16847548, and rs10494366) were genotyped to assess the effect of variant alleles on QTc and on the incidence of cardiac events. We quantified the association between variant alleles, QTc, and outcomes to assess whether NOS1AP is a useful risk stratifier in LQTS. Results: Variant alleles tagged by SNPs rs4657139 and rs16847548 were associated with an average QTc prolongation of 7 and 8 ms, respectively (p < 0.05; p < 0.01); whereas rs4657139 and rs10494366 were associated with increased incidence of cardiac events (25.2% vs. 18.0%, p < 0.05 and 24.8% vs. 17.8% p < 0.05). Cox multivariate analysis identified rs10494366 minor allele as an independent prognostic marker among patients with QTc <500 ms (hazard ratio: 1.63; 95% confidence interval: 1.06 to 2.5; p < 0.05) but not in the entire cohort. Conclusions: Our results provide the first demonstration, to our knowledge, of a risk-conferring genetic modifier in a large LQTS cohort. Subject to confirmation in additional cohorts, we suggest that the NOS1AP tag SNP genotype may provide an additional clinical dimension, which helps assess risk and choice of therapeutic strategies in LQTS.

Original languageEnglish (US)
Pages (from-to)2745-2752
Number of pages8
JournalJournal of the American College of Cardiology
Volume55
Issue number24
DOIs
StatePublished - Jun 15 2010

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Keywords

  • cardiac arrhythmias
  • genetics
  • long QT syndrome
  • risk stratification
  • single nucleotide polymorphisms

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Tomás, M., Napolitano, C., De Giuli, L., Bloise, R., Subirana, I., Malovini, A., Bellazzi, R., Arking, D. E., Marban, E., Chakravarti, A., Spooner, P. M., & Priori, S. G. (2010). Polymorphisms in the NOS1AP Gene Modulate QT Interval Duration and Risk of Arrhythmias in the Long QT Syndrome. Journal of the American College of Cardiology, 55(24), 2745-2752. https://doi.org/10.1016/j.jacc.2009.12.065