on November 21, 2005
Published online before print November 21, 2005, doi: 10.1161/CIRCULATIONAHA.105.555474
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Submitted on April 12, 2005
From the Department of Health Sciences (M.D.T., N.A.S., P.R.B.), University of Leicester; the Department of Cardiovascular Sciences (S.M.R., P.B., C.B., J.O., D.C., J.G., S.H., T.S., C.R., N.J.S.), University of Leicester, Glenfield Hospital; and the Department of Genetics (M.D.T., N.A.S., P.R.B.), University of Leicester, Leicester; and the Department of Clinical Pharmacology and Barts and the London Genome Centre (S.N., M.C., P.B.M.), Barts and the London School of Medicine, London, England. * To whom correspondence should be addressed. E-mail: njs{at}le.ac.uk.
Background--Blood pressure (BP) is a heritable trait of major public health concern. The WNK1 and WNK4 genes, which encode proteins in the WNK family of serine-threonine kinases, are involved in renal electrolyte homeostasis. Mutations in the WNK1 and WNK4 genes cause a rare monogenic hypertensive syndrome, pseudohypoaldosteronism type II. We investigated whether polymorphisms in these WNK genes influence BP in the general population. Methods and Results--Associations between 9 single-nucleotide polymorphisms (SNPs) in WNK1 and 1 in WNK4 with ambulatory BP were studied in a population-based sample of 996 subjects from 250 white European families. The heritability estimates of mean 24-hour systolic BP (SBP) and diastolic BP (DBP) were 63.4% and 67.9%, respectively. We found statistically significant (P<0.05) associations of several common SNPs and haplotypes in WNK1 with mean 24-hour SBP and/or DBP. The minor allele (C) of rs880054, with a frequency of 44%, reduced mean 24-hour SBP and DBP by 1.37 (95% confidence interval, -2.45 to -0.23) and 1.14 (95% confidence interval, -1.93 to -0.38) mm Hg, respectively, per copy of the allele. Conclusions--Common variants in WNK1 contribute to BP variation in the general population. This study shows that a gene causing a rare monogenic form of hypertension also plays a significant role in BP regulation in the general population. The findings provide a basis to identify functional variants of WNK1, elucidate any interactions of these variants with dietary intake or with response to antihypertensive drugs, and determine their impact on cardiovascular morbidity and mortality.
Revised on July 26, 2005
Accepted on August 22, 2005
Association of WNK1 Gene Polymorphisms and Haplotypes With Ambulatory Blood Pressure in the General Population
Martin D. Tobin PhD,
Key words: blood pressure • genetics • hypertension • kidney • risk factors
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