rs10494366, a SNP in the NOS1AP gene encoding the nitric oxide synthase I adaptor protein, accounts for some of the variation seen in abnormal heart rhythms, in particular, the QT interval. Based on studies totaling ~4,000 individuals of Caucasian ancestry, homozygotes for one allele have shorter QT intervals, while homozygotes for the other allele have a longer QT interval. [PMID 16648850]
A follow-up study determined that one rs10494366(G) allele was associated with a 3.8-ms (CI: 3.0 - 4.6ms, p=7.8x10(-20)) increase in QT interval duration, and two (G) alleles had twice that increase. No increase in risk for sudden death due to a cardiac problem was associated with this SNP, though. [PMID 17576865]
[PMID 18235038] rs10494366 minor homozygotes had a 9.3 msec longer QT interval compared to major homozygotes (p=5.7x10(-5)); rs10918594 minor homozygotes had a 12.5 msec longer QT interval compared to major homozygotes (p=1.5x10(-6)). Restricting analyses to the diabetic EAs strengthened the effect despite the reduction in sample size (11.3 msec difference, p=5.1x10(-5); 13.9 msec difference, p=1.6x10(-6), respectively).
[PMID 18551039] Patients with rs10494366(G;T) or (G;G) genotypes have an increased mortality risk (hazard ratio 2.8) compared to (T;T) genotypes upon treatment with sulfonylurea antidiabetic drugs. Glibenclamide is less effective in reducing glucose levels and mortality rates were higher compared with glibenclamide users with the (T;T) genotype. However, in tolbutamide and glimepiride users, the (G;T) and (G;G) genotypes were associated with a reduced mortality rate.
[PMID 19204306] rs10494366, rs4657139 and rs16847548 were significantly associated with adjusted QT interval in whites. relative hazard of SCD associated with each C allele at rs16847548 was 1.31. rs12567209 was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). No significant associations observed in blacks.
|Condition||QT interval prolongation|
|95% CI||7.90 (NR) msec difference between homozygote|
[PMID 19247217] Calcium channel blockers, NOS1AP, and heart-rate-corrected QT prolongation
[PMID 19943157] NOS1AP variant associated with incidence of type 2 diabetes in calcium channel blocker users in the Atherosclerosis Risk in Communities (ARIC) study
[PMID 19289301] SNP association and sequence analysis of the NOS1AP gene in SIDS
|Title||Several common variants modulate heart rate, PR interval and QRS duration|
|Odds Ratio||12.20 [9.72-14.68] % SD increase|
[PMID 20215044] Relationship of Common Candidate Gene Variants to Electrocardiographic T-Wave Peak to T-Wave End Interval and T-Wave Morphology Parameters
[PMID 20538168] Polymorphisms in the NOS1AP Gene Modulate QT Interval Duration and Risk of Arrhythmias in the Long QT Syndrome
[PMID 20722683] A common variant of NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes
[PMID 21663814] 5 HT(3)-receptor antagonists and cardiac repolarization time in patients expressing a novel genetic target associated with baseline QTc interval abnormalities
[PMID 22133205] Allelic variant of NOS1AP effects on cardiac alternans of repolarization during exercise testing
[PMID 17903306] Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study.
[PMID 18785031] Common variation in NOS1AP and KCNH2 genes and QT interval duration in young adults. The Cardiovascular Risk in Young Finns Study.
[PMID 18852197] Metabolic and cardiovascular traits: an abundance of recently identified common genetic variants.
[PMID 19019189] Common candidate gene variants are associated with QT interval duration in the general population.
[PMID 19076153] A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers.
[PMID 19180230] Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.
[PMID 19305408] Common variants at ten loci influence QT interval duration in the QTGEN Study.
[PMID 19389826] Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q.
[PMID 19587794] Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.
[PMID 20031603] A genome-wide association scan of RR and QT interval duration in 3 European genetically isolated populations: the EUROSPAN project.
[PMID 20305679] A variation in NOS1AP gene is associated with repaglinide efficacy on insulin resistance in type 2 diabetes of Chinese.
[PMID 22019493] Cardiac levels of NOS1AP RNA from right ventricular tissue recovered during lead extraction.
|qualified_impact||Insufficiently evaluated pathogenic|