Human Molecular Genetics Advance Access published online on October 16, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn341
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Identification of a Common Variant at the NOS1AP Locus Strongly Associated to QT – Interval Duration
1 Department of Epidemiology, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands 2 Department of Internal Medicine, Erasmus Medical Center, 3000CA, Rotterdam, The Netherlands 3 Department of Medical Informatics, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands 4 Member of the Netherlands Consortium on Healthy Aging (NCHA) 5 Inspectorate of Health Care, 2511 VX, The Hague, The Netherlands
* Corresponding author: Department of Epidemiology, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands, E-mail: b.stricker{at}erasmusmc.nl, Telephone: +31 10 7043482, Fax: +31 10 7044657
Received July 17, 2008; Revised October 14, 2008; Accepted October 14, 2008
QT-interval prolongation is an electrophysiologic phenomenon associated with sudden cardiac death. The QT-interval in the general population is for about 35% heritable. In genome-wide association studies a common variant (rs10494366T>G) within the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was identified and consistently associated with QT-interval duration. Yet, the causal variant remains unclear. Therefore, we performed fine mapping of the association of the NOS1AP locus with QT-interval within the Rotterdam Study, a population–based, prospective cohort study of individuals 
55 years of age. First, we tested the association of single-nucleotide polymorphisms (SNPs) in or within ±100kb of the NOS1AP gene with QT-interval duration, using sex – specific unstandardized residuals after regression on age and RR-interval, in 385 individuals using the combined set of SNPs present in the Affymetrix 500 k and Illumina 550 k chip arrays. Subsequently, we examined correspondence of the association signals in 4,606 individuals using the Illumina 550 k array. A C-to-T SNP at chromosome 1 position 160300514 (rs12143842, T-allele frequency=24%) was associated with a QT-interval duration increase of 4.4-ms. per additional T-allele (P=4.4x10–28). For comparison, the most strongly associated variant to date, rs10494366T>G, was associated with a 3.5-ms. increase (P=1.6x10–23) per additional G-allele. None of the inferred haplotypes showed a stronger effect than the individual rs12143842C>T SNP. In conclusion, we found rs12143842 6kb upstream distance of NOS1AP to be more strongly associated to QT-interval duration than rs10494366T>G. Functional analysis of this marker is warranted.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Eijgelsheim, C. Newton-Cheh, A. L.H.J. Aarnoudse, C. van Noord, J. C.M. Witteman, A. Hofman, A. G. Uitterlinden, and B. H.C. Stricker Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study Hum. Mol. Genet., November 1, 2009; 18(21): 4213 - 4218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Crotti, M. C. Monti, R. Insolia, A. Peljto, A. Goosen, P. A. Brink, D. A. Greenberg, P. J. Schwartz, and A. L. George Jr NOS1AP Is a Genetic Modifier of the Long-QT Syndrome Circulation, October 27, 2009; 120(17): 1657 - 1663. [Abstract] [Full Text] [PDF]
|
|