Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion

Newhouse, S. et al. (2009) Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion. PLoS ONE, 4(4), e5003. (doi:10.1371/journal.pone.0005003)

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Publisher's URL: http://dx.doi.org/10.1371/journal.pone.0005003

Abstract

WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p<10−7). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (>10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dominiczak, Professor Anna and Connell, Professor John and Brunner, Dr Eric
Authors: Newhouse, S., Farrall, M., Wallace, C., Hoti, M., Burke, B., Howard, P., Onipinla, A., Lee, K., Shaw-Hawkins, S., Dobson, R., Brown, M., Samani, N. J., Dominiczak, A. F., Connell, J. M., Lathrop, G. M., Kooner, J., Chambers, J., Elliott, P., Clarke, R., Collins, R., Laan, M., Org, E., Juhanson, P., Veldre, G., Viigimaa, M., Eyheramendy, S., Cappuccio, F. P., Ji, C., Iacone, R., Strazzullo, P., Kumari, M., Marmot, M., Brunner, E., Caulfield, M., and Munroe, P. B.
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:04 April 2009
Copyright Holders:Copyright © 2009 Public Library of Science
First Published:First published in PLoS ONE 4(4):e5003
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