Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study.
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.
Eijgelsheim
Mark
M
Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Newton-Cheh
Christopher
C
Aarnoudse
Adrianus L H J
AL
van Noord
Charlotte
C
Witteman
Jacqueline C M
JC
Hofman
Albert
A
Uitterlinden
André G
AG
Stricker
Bruno H C
BH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000453:epidemiology*; D004562:Electrocardiography; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006339:Heart Rate; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human