A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization.

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

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. 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.

Sudden cardiac death: The larger problem... The larger genome.

This perspective considers progress in understanding how genetic influences modulate susceptibility to lethal ventricular arrhythmias in cardiac patients and the population at large, as opposed to those with rare inherited arrhythmic conditions, such as the Long-QT and Brugada syndromes. It addresses largely unresolved issues, such as how important these effects may be and what we know of underlying mediators and pathways. Attention is given to newly revealed mechanisms of genomic function and the problem of identifying new susceptibility genes and targets useful in developing improved strategies for sudden death prevention.

Genomics in sudden cardiac death.

Sudden cardiac death (SCD) remains a public health problem of major magnitude. Contrary to earlier expectations, and despite decreased overall cardiac mortality, SCD rates appear to be rising in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. With the exception of the implantable defibrillator, there are few effective approaches to SCD prevention and even fewer clues concerning patient phenotypes predisposed to life-threatening arrhythmias. Clinical variables such as ejection fraction predict mortality but are not sensitive enough to identify many high SCD risk patients. The predictive power of autonomic dysregulation and markers such as lipid levels, hypertension, diabetes, and smoking is quite low in subclinical heart disease, the population in which the majority of SCDs occur. This review addresses advances in genomic science applicable to the SCD public health problem in both rare and common forms of heart disease. These include novel bioinformatic approaches to both identify candidate genes/pathways and identify previously unknown functional genetic elements, as well as methods to comprehensively screen these elements. We also discuss the possibility of applying high-density genome-wide SNP analyses to examine genetic contributions to arrhythmia susceptibility in community-based, case-control studies of common forms of SCD. The development of novel strategies to identify contributors to susceptibility in common cardiac phenotypes is most likely to lead to new and relevant therapeutic targets for SCD.

Screening entire health system ECG databases to identify patients at increased risk of death.

BACKGROUND: Current methods to identify patients at higher risk for sudden cardiac death, primarily left ventricular ejection fraction ≤35%, miss ≈80% of patients who die suddenly. We tested the hypothesis that patients with elevated QRS-scores (index of myocardial scar) and wide QRS-T angles (index abnormal depolarization-repolarization relationship) have high 1-year all-cause mortality and could be further risk stratified with clinical characteristics. METHODS AND RESULTS: We screened all 12-lead ECGs over 6 months at 2 large hospital systems and analyzed clinical characteristics and 1-year mortality. Patients with ECGs obtained in hospital areas with known high mortality rates were excluded. At the first hospital, QRS-score ≥5 and QRS-T angle ≥105° identified 8.0% of patients and was associated with an odds ratio of 2.79 (95% confidence interval, 2.10-3.69) for 1-year mortality compared with patients below both ECG thresholds (13.9% versus 5.5% death rate). Left ventricular ejection fraction was >35% in 82% of the former group of patients, and addition of ECG measures to left ventricular ejection fraction increased the discrimination of death risk (P<0.0001). At the second hospital, the odds ratio was 2.42 (1.95-3.01) for 1-year mortality (8.8% versus 3.8%). Adjustment for patient characteristics eliminated interhospital differences. Multivariable adjusted odds ratio combining data from both hospitals was 1.53 (1.28-1.83). Increasing heart rate and chronic renal impairment further predicted mortality. CONCLUSIONS: Screening hospital ECG databases with QRS-scoring and QRS-T angle analysis identifies patients with high 1-year all-cause mortality and predominantly preserved left ventricular ejection fraction. This approach may represent a widely available method to identify patients at increased risk of death.

Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome.

OBJECTIVES: We investigated the role of nitric oxide 1 adaptor protein (NOS1AP) as a genetic modifier of long QT syndrome (LQTS). BACKGROUND: LQTS risk stratification is complicated by the phenotype variability that limits prediction of life-threatening arrhythmic events based on available metrics. Thus, the identification of new markers is desirable. Recent studies have shown that NOS1AP variations in the gene modulate QT interval in healthy and 1 LQTS kindred, and occurrence of cardiac events in healthy subjects. METHODS: The study included 901 patients enrolled in a prospective LQTS registry. Three NOS1AP marker SNPs (rs4657139, rs16847548, and rs10494366) were genotyped to assess the effect of variant alleles on QTc and on the incidence of cardiac events. We quantified the association between variant alleles, QTc, and outcomes to assess whether NOS1AP is a useful risk stratifier in LQTS. RESULTS: Variant alleles tagged by SNPs rs4657139 and rs16847548 were associated with an average QTc prolongation of 7 and 8 ms, respectively (p < 0.05; p < 0.01); whereas rs4657139 and rs10494366 were associated with increased incidence of cardiac events (25.2% vs. 18.0%, p < 0.05 and 24.8% vs. 17.8% p < 0.05). Cox multivariate analysis identified rs10494366 minor allele as an independent prognostic marker among patients with QTc <500 ms (hazard ratio: 1.63; 95% confidence interval: 1.06 to 2.5; p < 0.05) but not in the entire cohort. CONCLUSIONS: Our results provide the first demonstration, to our knowledge, of a risk-conferring genetic modifier in a large LQTS cohort. Subject to confirmation in additional cohorts, we suggest that the NOS1AP tag SNP genotype may provide an additional clinical dimension, which helps assess risk and choice of therapeutic strategies in LQTS.

Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA. METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01). CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.