Document Detail

Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration.
MedLine Citation:
PMID:  18927126     Owner:  NLM     Status:  MEDLINE    
QT-interval prolongation is an electrophysiologic phenomenon associated with sudden cardiac death. The QT-interval in the general population is approximately 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 > or =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.
Mark Eijgelsheim; Adrianus L H J Aarnoudse; Fernando Rivadeneira; Jan A Kors; Jacqueline C M Witteman; Albert Hofman; Cornelia M van Duijn; André G Uitterlinden; Bruno H C Stricker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-10-16
Journal Detail:
Title:  Human molecular genetics     Volume:  18     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-22     Completed Date:  2009-02-03     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  347-57     Citation Subset:  IM    
Department of Epidemiology, Erasmus Medical Center 3000, CA, Rotterdam, The Netherlands.
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MeSH Terms
Adaptor Proteins, Signal Transducing / genetics*
European Continental Ancestry Group / genetics
Genome-Wide Association Study*
Long QT Syndrome / genetics*,  physiopathology*
Middle Aged
Polymorphism, Single Nucleotide
Prospective Studies
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/NOS1AP protein, human

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