Targeting 160 candidate genes for blood pressure regulation with a genome-wide genotyping array

Sõber, S. et al. (2009) Targeting 160 candidate genes for blood pressure regulation with a genome-wide genotyping array. PLoS ONE, 4(6), e6034. (doi:10.1371/journal.pone.0006034)

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Publisher's URL: http://dx.doi.org/10.1371/journal.pone.0006034

Abstract

The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region±10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P <10−3) were detected for the genes, where >50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15×10−5), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5×10−5) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20×10−5). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P<10−3) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dominiczak, Professor Anna and Connell, Professor John
Authors: Sõber, S., Org, E., Kepp, K., Juhanson, P., Eyheramendy, S., Gieger, C., Lichtner, P., Klopp, N., Veldre, G., Viigimaa, M., Döring, A., Putku, M., Kelgo, P., Shaw-Hawkins, S., Howard, P., Onipinla, A., Dobson, R. J., Newhouse, S. J., Brown, M., Dominiczak, A., Connell, J., Samani, N., Farrall, M., Caulfield, M. J., Munroe, P. B., Illig, T., Wichmann, H.-E., Meitinger, T., and Laan, M.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Published Online:29 June 2009
Copyright Holders:Copyright © 2009 Public Library of Science
First Published:First published in PLoS ONE 4(6):e6034
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874/71954Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874/92665Institute of Cardiovascular and Medical Sciences