Title : Polymorphisms in the WNK 1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion

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 = 7610, combined with BRIGHT data-set p = 2610, 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). 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. Citation: Newhouse S, Farrall M, Wallace C, Hoti M, Burke B, 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 Editor: Florian Kronenberg, Innsbruck Medical University, Austria Received December 16, 2008; Accepted February 5, 2009; Published April 4, 2009 Copyright: 2009 Newhouse et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The HYPEST sample collection was financed by Wellcome Trust International Senior Research Fellowship to Maris Laan (grant no. 070191/Z/03/Z) in Biomedical Science in Central Europe and by Estonian Ministry of Education and Science core grant no. 0182721s06. The BRIGHT study and current work are supported by the Medical Research Council of Great Britain (grant number; G9521010D) and the British Heart Foundation (grant number PG02/128). CW is funded by the British Heart Foundation (grant number: FS/05/061/19501). SJN is funded by the Medical Research Council and The William Harvey Research Foundation. Profs Dominiczak and Samani are British Heart Foundation Chairholders. The LOLIPOP Study was funded by the British Heart Foundation. The Whitehall II study has been supported by grants from the Medical Research Council; Economic and Social Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (HL36310), US, NIH: National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. Samples from the English Longitudinal Study of Ageing (ELSA) DNA Repository (EDNAR), received support under a grant (AG1764406S1) awarded by the National Institute on Aging (NIA). ELSA was developed by a team of researchers based at the National Centre for Social Research, University College London and the Institute of Fiscal Studies. The data were collected by the National Centre for Social Research. The developers and funders of ELSA and the Archive do not bear any responsibility for the analyses or interpretations presented here. Michael Marmot is supported by a MRC Research Professorship. The Whitehall-1 study was supported by the British Heart Foundation and Medical Research Council. The funders of this work did not take part in study design, data collection, or analysis of these data. In addition, none of the funders took part in the decision to publish, or in preparation of this manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: p.b. munroe@qmul.ac. uk PLoS ONE | www.plosone. org 1 April 2009 | Volume 4 | Issue 4 | e5003