on June 18, 2007
Published online before print June 18, 2007, doi: 10.1161/CIRCULATIONAHA.106.676783
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 16, 2006
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. * To whom correspondence should be addressed. E-mail: b.stricker{at}erasmusmc.nl.
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 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.
Accepted on May 1, 2007
Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study
Albert-Jan L.H.J. Aarnoudse MD,
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.
Key words: arrhythmia • death, sudden • electrocardiography • genetics • long-QT syndrome
This article has been cited by other articles:
 |
|
 |
|
  K. Ueda, C. Valdivia, A. Medeiros-Domingo, D. J. Tester, M. Vatta, G. Farrugia, M. J. Ackerman, and J. C. Makielski Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex PNAS, July 8, 2008; 105(27): 9355 - 9360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D Tobin, M. Kahonen, P. Braund, T. Nieminen, C. Hajat, M. Tomaszewski, J. Viik, R. Lehtinen, G A. Ng, P. W Macfarlane, et al. Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations Int. J. Epidemiol., May 29, 2008; (2008) dyn091v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Lehtinen, C. Newton-Cheh, J. T. Ziegler, C. D. Langefeld, B. I. Freedman, K. R. Daniel, D. M. Herrington, and D. W. Bowden Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study Diabetes, April 1, 2008; 57(4): 1108 - 1114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-C. Chang, A. S. Barth, T. Sasano, E. Kizana, Y. Kashiwakura, Y. Zhang, D. B. Foster, and E. Marban CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart PNAS, March 18, 2008; 105(11): 4477 - 4482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Herring and D. J Paterson Letter by Herring and Paterson Regarding Article, "Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study" Circulation, December 11, 2007; 116(24): e564 - e564. [Full Text] [PDF]
|
|
|
|
|
|
A.-J. L.H.J. Aarnoudse, S. M.J.M. Straus, A. Hofman, A. G. Uitterlinden, J. C.M. Witteman, B. H.C. Stricker, C. Newton-Cheh, J. A. Kors, and P. I.W. de Bakker Response to Letter Regarding Article, "Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study" Circulation, December 11, 2007; 116(24): e565 - e565. [Full Text] [PDF]
|
|
|
|
|
|
F. Cambien and L. Tiret Genetics of Cardiovascular Diseases: From Single Mutations to the Whole Genome Circulation, October 9, 2007; 116(15): 1714 - 1724. [Full Text] [PDF]
|
|
|
|
|
|
C. Newton-Cheh, C.-Y. Guo, M. G. Larson, S. L. Musone, A. Surti, A. L. Camargo, J. A. Drake, E. J. Benjamin, D. Levy, R. B. D'Agostino Sr, et al. Common Genetic Variation in KCNH2 Is Associated With QT Interval Duration: The Framingham Heart Study Circulation, September 4, 2007; 116(10): 1128 - 1136. [Abstract] [Full Text] [PDF]
|
|