Published online before print June 18, 2007, doi: 10.1161/CIRCULATIONAHA.106.676783
(Circulation. 2007;116:10-16.)
© 2007 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study
From the Departments of Epidemiology and Biostatistics (A.L.H.J.A., S.M.J.M.S, A.H., A.G.U., J.C.M.W., B.H.C.S.), Internal Medicine (A.G.U., B.H.C.S.), and Medical Informatics (J.A.K.), Erasmus Medical Center, Rotterdam, the Netherlands; Cardiology Division (C.N.-C.), Department of Molecular Biology (P.I.W.d.B.), and Center for Human Genetics Research (P.I.W.d.B.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (C.N.-C., P.I.W.d.B.), Broad Institute of Harvard and MIT, Cambridge, Mass; National Heart, Lung, and Blood Institute’s Framingham Heart Study (C.N.-C.), Framingham, Mass; Department of Genetics, Harvard Medical School (P.I.W.d.B.), Boston, Mass; Inspectorate for Health Care (A.L.H.J.A., B.H.C.S.), the Hague, the Netherlands; and Dutch Medicines Evaluation Board (S.M.J.M.S), the Hague, the Netherlands.
Correspondence to Bruno H.C. Stricker, PhD, Department of Epidemiology and Biostatistics, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. E-mail b.stricker{at}erasmusmc.nl
Received November 16, 2006; accepted May 1, 2007.
Background— QT prolongation is an important risk factor for sudden cardiac death. About 35% of QT-interval variation is heritable. In a recent genome-wide association study, a common variant (rs10494366) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was found to be associated with QT-interval variation. We tested for association of 2 NOS1AP variants with QT duration and sudden cardiac death.
Methods and Results— The Rotterdam Study is a population-based, prospective cohort study of individuals 
55 years of age. The NOS1AP variants rs10494366 T>G and rs10918594 C>G were genotyped in 6571 individuals. Heart rate–corrected QT interval (QTc) was determined with ECG analysis software on up to 3 digital ECGs per individual (total, 11 108 ECGs from 5374 individuals). The association with QTc duration was estimated with repeated-measures analyses, and the association with sudden cardiac death was estimated by Cox proportional-hazards analyses. The rs10494366 G allele (36% frequency) was associated with a 3.8-ms (95% confidence interval, 3.0 to 4.6; P=7.8x10–20) increase in QTc interval duration for each additional allele copy, and the rs10918594 G allele (31% frequency) was associated with a 3.6-ms (95% confidence interval, 2.7 to 4.4; P=6.9x10–17) increase per additional allele copy. None of the inferred NOS1AP haplotypes showed a stronger effect than the individual single-nucleotide polymorphisms. There were 233 sudden cardiac deaths over 11.9 median years of follow-up. No significant association was observed with sudden cardiac death risk.
Conclusions— Common variants in NOS1AP are strongly associated with QT-interval duration in an elderly population. Larger sample sizes are needed to confirm or exclude an effect on sudden cardiac death risk.
CLINICAL PERSPECTIVE
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