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Nitric Oxide Synthase 1 Adaptor Protein, an Emerging New Genetic Marker for QT Prolongation and Sudden Cardiac Death.

ABSTRACT: UNLABELLED:Sudden cardiac death (SCD) is defined as sudden unexplained death due to cardiac causes with an acute change in cardiovascular status within 1 hour of onset of symptoms. Alternatively, in unwitnessed cases, SCD can also be defined as a person last seen functionally normal 24 hours before being found dead. Despite significant advances in understanding the pathophysiology of cardiovascular diseases and the resultant improvement in resuscitation science, SCD remains a major healthcare challenge worldwide. Although the most pronounced risk factor for SCD is the presence of coronary artery disease in the setting of a depressed left ventricular function, most deaths occur in the larger, lower-risk subgroups where genetic variations and other conditions may be the precipitating factors in triggering SCD. Recently, a common genetic variation in a neuronal nitric oxide synthase regulator, nitric oxide synthase 1 adaptor protein (NOS1AP) also known as carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (CAPON) gene, has been identified as a new genetic marker in modulating QT interval prolongation and SCD in general populations. Animal study revealed that NOS1AP is expressed in the heart and interacts with NOS1-NO pathways to modulate cardiac repolarization via suppressing the sarcolemmal L-type calcium current and enhancing the IKr current. This important genetic implication was soon replicated in other racial/ethnic populations and extended to a variety of clinical settings including diabetes mellitus, coronary artery disease, myocardial infarction, and congenital or drug-induced long QT syndrome. The purpose of this review aims to provide up-to-date information about the emerging new genetic marker, NOS1AP, in relation to QT prolongation and SCD. KEY WORDS:NOS1AP; QT interval; Sudden cardiac death.

SUBMITTER: Chang KC

PROVIDER: S-EPMC4804833 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Nitric Oxide Synthase 1 Adaptor Protein, an Emerging New Genetic Marker for QT Prolongation and Sudden Cardiac Death.

Chang Kuan-Cheng KC Sasano Tetsuo T Wang Yu-Chen YC Huang Shoei K Stephen SK

Acta Cardiologica Sinica 20130501 3

<h4>Unlabelled</h4>Sudden cardiac death (SCD) is defined as sudden unexplained death due to cardiac causes with an acute change in cardiovascular status within 1 hour of onset of symptoms. Alternatively, in unwitnessed cases, SCD can also be defined as a person last seen functionally normal 24 hours before being found dead. Despite significant advances in understanding the pathophysiology of cardiovascular diseases and the resultant improvement in resuscitation science, SCD remains a major healt ...[more]

PMID: 27122710

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Project description: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.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.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.

Dataset Information

Nitric Oxide Synthase 1 Adaptor Protein, an Emerging New Genetic Marker for QT Prolongation and Sudden Cardiac Death.

Publications

Nitric Oxide Synthase 1 Adaptor Protein, an Emerging New Genetic Marker for QT Prolongation and Sudden Cardiac Death.

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