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

• Published in: Journal of the American College of Cardiology Vol. 55; no. 24; pp. 2745 - 2752
• Main Authors: Tomás, Marta, PhD, Napolitano, Carlo, MD, PhD, De Giuli, Luciana, PhD, Bloise, Raffaella, MD, Subirana, Isaac, MS, Malovini, Alberto, MS, Bellazzi, Riccardo, PhD, Arking, Dan E., PhD, Marban, Eduardo, MD, PhD, Chakravarti, Aravinda, PhD, Spooner, Peter M., PhD, Priori, Silvia G., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 15.06.2010; Elsevier Limited
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Biological and medical sciences; Biomedical research; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Cardiovascular; Deoxyribonucleic acid; DNA; DNA - genetics; Electrocardiography; Female; Follow-Up Studies; Genes; Genetic Predisposition to Disease; Genotype; Haplotypes; Heart; Heart attacks; Heart rate; Humans; Incidence; Internal Medicine; Long QT syndrome; Long QT Syndrome - epidemiology; Long QT Syndrome - genetics; Long QT Syndrome - physiopathology; Male; Medical sciences; Mutation; Nitric oxide; Polymerase Chain Reaction; Polymorphism, Genetic; Prognosis; Prospective Studies; Risk Factors; Studies; Time Factors; risk stratification; long QT syndrome; single nucleotide polymorphism; CI; LQTS; ECG; HR; ICD; sudden cardiac death; electrocardiogram; genetics; MAF; minor allele frequency; SNP; SCD; NOS1AP; hazard ratio; nitric oxide 1 adaptor protein; confidence interval; single nucleotide polymorphisms; cardiac arrhythmias; implantable cardioverter-defibrillator; PCR; polymerase chain reaction; QT interval; Arrhythmia; Prolonged QT interval; Cardiovascular disease; Risk; Duration; Conduction disorder; Gene; Heart block; Heart disease; Risk factor; Circulatory system; Cardiology; Polymorphism
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2009.12.065

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.