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Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi187
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received February 17, 2005
Revised April 6, 2005
Accepted May 5, 2005

Article

Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension (BRIGHT) study

Stephen J Newhouse 1, Chris Wallace 1, Richard Dobson 1, Charles Mein 1, Janine Pembroke 1, Martin Farrall 2, David Clayton 3, Morris Brown 3, Nilesh Samani 4, Anna Dominiczak 5, John M Connell 5, John Webster 6, G Mark Lathrop 7, Mark Caulfield 1, and Patricia B Munroe 1*

1 Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Charterhouse Square, London, UK
2 Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK
3 Clinical Pharmacology and the Cambridge Institute of Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
4 Cardiology, University of Leicester, Glenfield Hospital, Leicester, UK
5 BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow, UK
6 Medicine and Therapeutics, Aberdeen Royal Infirmary, Aberdeen, UK
7 Centre National de Genotypage, Evry, France

* To whom correspondence should be addressed.
Patricia B Munroe, E-mail: p.b.munroe{at}qmul.ac.uk.


  Abstract

Mutations in the WNK1 gene cause Gordon's syndrome, a rare Mendelian form of hypertension. We assessed whether common WNK1 variants might also contribute to essential hypertension, a multifactorial disorder affecting over 25% of the adult population worldwide. A panel of 19 SNPs spanning the gene were selected from public databases and were genotyped in 100 white European families to determine the pattern of linkage disequilibrium, haplotype structure and tagging SNPs for the PRKWNK1 locus. Eight tagging SNPs were identified with 90% power to predict common WNK1 haplotypes and SNPs. Family-based association tests were used to test for association with essential hypertension and severity of hypertension in 712 severely hypertensive families from the MRC British Genetics of Hypertension study resource. No association was found between WNK1 polymorphisms or haplotypes with hypertension, however one SNP rs1468326, located 3kb from the WNK1 promoter was found to be nominally associated with severity of hypertension, with both systolic blood pressure (Z=+2.24, P=0.025) and diastolic blood pressure (Z=+1.99, P=0.046). We also found nominal support for association of one common WNK1 haplotype with increased systolic blood pressure (Z=+1.91, P=0.053). This is the first study to perform haplotype association analysis of the WNK1 gene with essential hypertension. This finding of association between a SNP near the promoter region and severity of hypertension, suggests that increased expression of WNK1 might contribute to blood pressure variability and susceptibility to essential hypertension, similar to the mechanism of hypertension observed in Gordon's syndrome.


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