Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations.
BACKGROUND
The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOS1AP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOS1AP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study.


RESULTS
We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs10494366 and rs4657139 in NOS1AP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOS1AP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs12567209, which was not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs16847548 and SCD, and such adjustment had no effect on the association between rs12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOS1AP and either QT interval or SCD were observed in blacks.


CONCLUSIONS
In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white US adults.
Kao
W H Linda
WH
Department of Epidemiology, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA.
Arking
Dan E
DE
Post
Wendy
W
Rea
Thomas D
TD
Sotoodehnia
Nona
N
Prineas
Ronald J
RJ
Bishe
Bryan
B
Doan
Betty Q
BQ
Boerwinkle
Eric
E
Psaty
Bruce M
BM
Tomaselli
Gordon F
GF
Coresh
Josef
J
Siscovick
David S
DS
Marbán
Eduardo
E
Spooner
Peter M
PM
Burke
Gregory L
GL
Chakravarti
Aravinda
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human