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-wideassociation 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 (PϽ0.0001). 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, Pϭ0.002), 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, Pϭ0.003). 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

Heritability of Risk for Sudden Cardiac Arrest in ESRD

“…In the general population, multiple SNPs have been identified that associate with an increased risk of cardiac arrest. [6][7][8] As such, it is possible that these same SNPs occur with increased frequency or have a magnified effect size in patients on dialysis as an explanation for the increased rate of cardiac arrest reported in the dialysis population. Alternatively, novel SNPs specific to patients with ESRD may explain the excess cardiovascular mortality.…”

“…4 The discovery of predictive markers for cardiac arrest in ESRD could alter the practice of nephrology, because the risk of cardiac arrest is 5% per year in the dialysis population. 2,5 In the general population, genome-wide association studies have identified genetic polymorphisms that significantly increase the risk of cardiac arrest [6][7][8] ; however, their clinical application has been limited, because the rate of cardiac arrest is only 0.24% per year. 9 As such, a doubling of risk in the general population would still be too low to warrant empirical primary prevention therapy.…”

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

“…Noteworthy, NOS1AP SNPs reached higher significance compared with SNPs in genes known to be causes of LQTS and SQTS (306,343). Furthermore, NOS1AP has been linked to sudden cardiac death (205,326).…”

Risk Stratification for Sudden Cardiac Death

“…A number of genetic variants have been linked to rare, heritable arrhythmias and SCD not associated with coronary disease, 46,47 and some (eg, ion channel variants associated with QT duration) were viewed as candidates of interest for familial patterns of SCD in coronary heart disease. Although these candidates have not January 28, 2014 yet emerged as targets for risk prediction in SCD attributable to coronary heart disease, other common gene variants have been linked to SCD 48,49 or to surrogate, mainly electrocardiographic risk factors, in apparently healthy populations. [50][51][52] Alternative pathways that appear to modulate QT duration are among these, as are associations that do not necessarily involve QT control.…”