Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome.
OBJECTIVE
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.
Tomás
Marta
M
Molecular Cardiology Laboratories, IRCCS Salvatore Maugeri Foundation, Pavia, Italy.
Napolitano
Carlo
C
De Giuli
Luciana
L
Bloise
Raffaella
R
Subirana
Isaac
I
Malovini
Alberto
A
Bellazzi
Riccardo
R
Arking
Dan E
DE
Marban
Eduardo
E
Chakravarti
Aravinda
A
Spooner
Peter M
PM
Priori
Silvia G
SG
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D004247:DNA / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D008133:Long QT Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human; D004247:DNA