Rs10494366

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.

GWAS
SNP	rs10494366
PubMedID	[PMID 16648850]
Condition	QT interval prolongation
Gene	NOS1AP
Risk Allele
pValue	1.00E-010
OR	4.9
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

GWAS snp
PMID	[PMID 20062063]
Trait	Electrocardiographic traits
Title	Several common variants modulate heart rate, PR interval and QRS duration
Risk Allele	G
P-val	5E-22
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