Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study
Open Access
- 30 July 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 18 (21), 4213-4218
- https://doi.org/10.1093/hmg/ddp356
Abstract
Common variation within the nitric oxide-1 synthase activator protein ( NOS1AP ) locus is strongly related to QT interval, a sudden cardiac death (SCD) risk factor. A recent report describes common variation in NOS1AP associated with SCD in a US population of European ancestry. The objective of the current study was to obtain additional evidence by investigating the association between NOS1AP variants and SCD in the prospective population-based Rotterdam Study. The study population consisted of 5974 European ancestry subjects, aged 55 years and older, genotyped on Illumina arrays. SCD was defined according to European Society of Cardiology guidelines. Smoking, body mass index, diabetes mellitus, hypertension, heart failure and myocardial infarction were used as covariates in Cox proportional hazard models. Results were combined with reported evidence using inverse-variance weighted meta-analysis. Two hundred and eight (109 witnessed) cases of SCD occurred during a mean follow-up of 10.4 years. Within the Rotterdam Study alone, no significant associations were observed. Upon pooling of results with existing data, we observed strengthening of existing evidence for rs16847549 (US data HR = 1.31, P = 0.0024; Rotterdam Study HR = 1.18, P = 0.16; joint HR = 1.26, P = 0.0011). When the case definition in the Rotterdam Study was restricted to witnessed SCD, association of rs16847549 with SCD became stronger (joint P = 0.00019) and additionally the association between rs12567209 and SCD gained significance (US data HR = 0.57, P = 0.0035; Rotterdam Study HR = 0.69, P = 0.23; joint HR = 0.60, P = 0.0018). In conclusion, this study provided additional evidence for association between genetic variation within NOS1AP and SCD. The mechanism by which this effect is exerted remains to be elucidated.Keywords
This publication has 34 references indexed in Scilit:
- Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association StudiesPLOS ONE, 2009
- Common variants at ten loci influence QT interval duration in the QTGEN StudyNature Genetics, 2009
- Common variants at ten loci modulate the QT interval duration in the QTSCD StudyNature Genetics, 2009
- Genetic Variations in Nitric Oxide Synthase 1 Adaptor Protein Are Associated With Sudden Cardiac Death in US White Community-Based PopulationsCirculation, 2009
- Practical aspects of imputation-driven meta-analysis of genome-wide association studiesHuman Molecular Genetics, 2008
- CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heartProceedings of the National Academy of Sciences, 2008
- The Rotterdam Study: objectives and design updateEuropean Journal of Epidemiology, 2007
- Associations between Genetic Variants in the NOS1AP (CAPON) Gene and Cardiac Repolarization in the Old Order AmishHuman Heredity, 2007
- Genetic Variation, C-Reactive Protein Levels, and Incidence of DiabetesDiabetes, 2007
- A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarizationNature Genetics, 2006