Human Molecular Genetics Advance Access originally published online on October 16, 2008
Human Molecular Genetics 2009 18(2):347-357; doi:10.1093/hmg/ddn341
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Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration
1 Department of Epidemiology 2 Department of Internal Medicine 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
* To whom correspondence should be addressed at: Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. Tel: +31 107043482; Fax: +31 107044657; Email: b.stricker{at}erasmusmc.nl
Received July 17, 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 
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 of 
55 years of age. First, we tested the association of single-nucleotide polymorphisms (SNPs) in or within ±100 kb 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 500k and Illumina 550k chip arrays. Subsequently, we examined correspondence of the association signals in 4606 individuals using the Illumina 550k 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 = 4.4 x 10–28). For comparison, the most strongly associated variant to date, rs10494366T > G, was associated with a 3.5 ms increase (P = 1.6 x 10–23) per additional G-allele. None of the inferred haplotypes showed a stronger effect than the individual rs12143842C > T SNP. In conclusion, we found rs12143842 6 kb upstream distance of NOS1AP to be more strongly associated to QT-interval duration than rs10494366T > G. Functional analysis of this marker is warranted.
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