Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations

Abstract

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.

Methods and 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.

Figure 1

Plots showing the linkage disequilibrium (LD) pattern and association results for both QT interval and SCD in whites (A) and blacks (B) for 19 SNPs genotyped to tag the NOS1AP locus and surrounding region that exhibited the strongest association with QT interval in previous studies. The bottom panel is a plot showing the pairwise LD between SNPs. The value within each diamond represents the pair-wise correlation between SNPs (measured as R-square) defined by the top left and the top right sides of the diamond. Shading represents the magnitude and significance of the pair-wise LD, with a black to white gradient reflecting higher to lower LD values; see http://www.broad.mit.edu/mpg/haploview/ for further details. NOS1AP exons 1 and 2 are shown in orange. The top panel is a plot showing the significance for each SNP, with genomic position on the X-axis and the negative base-10 logarithm of the p-value on the Y-axis. Information regarding genomic position was taken from Human Genome Build 35.

Figure 1

Plots showing the linkage disequilibrium (LD) pattern and association results for both QT interval and SCD in whites (A) and blacks (B) for 19 SNPs genotyped to tag the NOS1AP locus and surrounding region that exhibited the strongest association with QT interval in previous studies. The bottom panel is a plot showing the pairwise LD between SNPs. The value within each diamond represents the pair-wise correlation between SNPs (measured as R-square) defined by the top left and the top right sides of the diamond. Shading represents the magnitude and significance of the pair-wise LD, with a black to white gradient reflecting higher to lower LD values; see http://www.broad.mit.edu/mpg/haploview/ for further details. NOS1AP exons 1 and 2 are shown in orange. The top panel is a plot showing the significance for each SNP, with genomic position on the X-axis and the negative base-10 logarithm of the p-value on the Y-axis. Information regarding genomic position was taken from Human Genome Build 35.

Figure 2

Cumulative incidence curves, accounting for competing cause of death, in whites. Kaplan-Meier survival curves in whites by rs16847548 (A,C,E) and by rs1267209 (B,D,F). (A,B) SCD, (C,D) non-SCD CHD mortality, and (E,F) non-SCD & non-CHD mortality. For rs16847548, green lines represent CC, red lines represent CT, and blue lines represent TT. For rs12567209, green lines represent AA, red lines represent AG, and blue lines represent GG. Only 1 CHD death was observed in rs12567209 AA individuals (D), and hence no curve is shown for that genotype.