The electrocardiographic 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 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 (ARIC) study and the Cardiovascular Health Study (CHS).
Methods and Results
We examined 19 tagging SNPs 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 SNPs in NOS1AP, including rs10494366, rs4657139, and rs16847548 were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjusting for age, sex, and study, the relative hazard (RH) of SCD associated with each C allele at rs16847548 was 1.31 (95% CI: 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring SNP, rs12567209, not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (RH = 0.57, 95%CI: 0.39, 0.83; P = 0.003). Adjustment for QT interval and CHD 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 SNPs in NOS1AP and either QT interval or SCD were observed in blacks.
In a combined analysis of two population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white U.S. adults.