Common
            <i>NOS1AP</i>
            Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study

Aarnoudse, Albert-Jan L.H.J.; Newton‐Cheh, Christopher; Bakker, Paul I. W. de; Straus, Sabine M. J. M.; Kors, Jan A.; Hofman, Albert; Uitterlinden, André G.; Witteman, Jacqueline C. M.; Stricker, Bruno H.

doi:10.1161/circulationaha.106.676783

Cited by 128 publications

(102 citation statements)

References 46 publications

(34 reference statements)

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“…This association was replicated in two other population-based studies (11), an elderly population (12) and the genetically more homogeneous Old Order Amish population (13). However, the propensity for false-positive reports in genetic association studies warrants replication in additional cohorts: especially cohorts with high risk for prolonged QT interval and SCD due to competing factors, such as diabetes and coronary disease.…”

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confidence: 78%

Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study

et al. 2008

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OBJECTIVES—Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with QT interval duration in a type 2 diabetes–enriched sample of European ancestry. RESEARCH DESIGN AND METHODS—Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications. RESULTS—In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes (P = 5.7 × 10−5); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes (P = 1.5 × 10−6). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms difference, P = 5.1 × 10−5; 13.9-ms difference, P = 1.6 × 10−6, respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans. CONCLUSIONS—Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.

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confidence: 78%

Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study

et al. 2008

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“…NOS1AP variants have been shown to be strongly associated with the QT interval and the risk of sudden cardiac death in elderly Hollanders (Aarnoudse et al, 2007), the South African LQTS population (Crotti et al, 2009), and the Rotterdam Study (Eijgelsheim et al, 2009a(Eijgelsheim et al, , 2009b. Interestingly, two independent studies have confirmed that an NOS1AP variant is associated with the QT interval duration in Chinese (Lu et al, 2010;Qin et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Positive Association Between rs10918859 of the NOS1AP Gene and Coronary Heart Disease in Male Han Chinese

Huang

Lian

Huang

et al. 2013

Genetic Testing and Molecular Biomarkers

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Westaway et al. have revealed a significant association between common variants of calsequestrin-2 (CASQ2) and nitric oxide synthase 1 (neuronal) adaptor protein (NOS1AP) and the risk of sudden death in patients of coronary heart disease (CHD). In light of the findings, we aim to explore the association between variants of the two genes and CHD risk in Han Chinese. Our results show a significant contribution of rs10918859 of the NOS1AP gene to CHD in Han Chinese (genotype: v 2 = 8.33, df = 2, p = 0.015; allele: v 2 = 4.00, df = 1, p = 0.047, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.00-2.05). The association of rs10918859 with CHD is seen only in men (genotype: v 2 = 7.81, df = 2, p = 0.02; allele: v 2 = 4.49, df = 1, p = 0.03, OR = 1.66, 95% CI = 1.03-2.66). Moreover, rs10918859 is likely to exert its effect under a dominant model in men (v 2 = 7.6, df = 1, p = 0.005, OR = 2.46, 95% CI = 1.29-4.71). No association is observed between CASQ2 variants and CHD risk. The frequencies of rs12084280-C and rs10918859-A are higher in Han Chinese (36.7% and 41.6%) than those in Europeans (11% and 19.4%, respectively). These ethnic differences imply that further validation of NOS1AP in the susceptibility of CHD in other populations is warranted. We confirm that rs10918859 of the NOS1AP gene is associated with CHD in Han Chinese. In addition, here we report a gender effect in the association between rs10918859 of the NOS1AP gene and CHD.

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“…10 SNPs selection and analysis. Candidate single nucleotide polymorphisms (SNPs) were selected among those previously described as modulating ECG intervals [11][12][13][14][15][16][17] or predisposition to arrhythmic events. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] In particular, most variants were located in genes encoding cardiac voltage-dependent channels (KCNQ1, KCNH2, SCN5A, KCNJ11, KCNE1, KCNE2, KCNJ2), structural proteins (ANK2, GJA5, PALLD), sympathetic system modulators (ADRB1, ADRB2, ADRB3), blood pressure regulators (NOS1AP, PAI-1), modulators of ionic flows (PLN, CERKL, SLCO3A1), transcription factors (BRUNOL4, LITAF), regulators of cell morphology (NRG3) and other genes known to be associated to ECG intervals modulation (MDR1, CASQ2, NDRG4, NUBPL, RNF207; Supplementary Table S2).…”

Section: Genetic Analysismentioning

confidence: 99%

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

Sommariva¹,

Pappone

Boneschi³

et al. 2013

Eur J Hum Genet

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Brugada syndrome is an inherited arrhythmogenic disorder leading to sudden death predominantly in the 3-4 decade. To date the only reliable treatment is the implantation of a cardioverter defibrillator; however, better criteria for risk stratification are needed, especially for asymptomatic subjects. Brugada syndrome genetic bases have been only partially understood, accounting for o30% of patients, and have been poorly correlated with prognosis, preventing inclusion of genetic data in current guidelines. We designed an observational study to identify genetic markers for risk stratification of Brugada patients by exploratory statistical analysis. The presence of genetic variants, identified by SCN5A gene analysis and genotyping of 73 candidate polymorphisms, was correlated with the occurrence of major arrhythmic events in a cohort of 92 Brugada patients by allelic association and survival analysis. In all, 18 mutations were identified in the SCN5A gene, including 5 novel, and statistical analysis indicated that mutation carriers had a significantly increased risk of major arrhythmic events (P ¼ 0.024). In addition, we established association of five polymorphisms with major arrhythmic events occurrence and consequently elaborated a pilot risk stratification algorithm by calculating a weighted genetic risk score, including the associated polymorphisms and the presence of SCN5A mutation as function of their odds ratio. This study correlates for the first time the presence of genetic variants with increased arrhythmic risk in Brugada patients, representing a first step towards the design of a new risk stratification model.

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Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study

Cited by 128 publications

References 46 publications

Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study

Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study

Positive Association Between rs10918859 of the NOS1AP Gene and Coronary Heart Disease in Male Han Chinese

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

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