Location of Repository

Association of WNK1 Gene Polymorphisms and Haplotypes With Ambulatory Blood Pressure in the General Population

By Martin D. Tobin, Stuart M. Raleigh, Stephen J. Newhouse, Peter S. Braund, Clare Bodycote, Jenny Ogleby, Deborah Cross, Jay Gracey, Saija Hayes, Terry Smith, Cathy Ridge, Mark J. Caulfield, Nuala A. Sheehan, Patricia B. Munroe, Paul R. Burton and Nilesh J. Samani

Abstract

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. \ud \ud 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. \ud \ud 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.Peer reviewedPublisher versio

Publisher: American Heart Association
Year: 2005
DOI identifier: 10.1161/CIRCULATIONAHA.105.555474
OAI identifier: oai:lra.le.ac.uk:2381/7342
Journal:

Suggested articles

Preview

Citations

  1. (2005). Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure. Stat Med. doi
  2. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. doi
  3. (2003). Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study. Hum Hered. doi
  4. (1998). Clinical significance not statistical significance: a simple Bayesian alternative to p values. doi
  5. (2003). Correcting for non-random ascertainment in generalized linear mixed models (GLMMs) fitted using Gibbs sampling. Genet Epidemiol. doi
  6. Effectiveness and costs of interventions to lower systolic blood pressure and cholesterol: a global and regional analysis on reduction of cardiovascular-disease risk. doi
  7. (2001). Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet; DASH-Sodium Collaborative Research Group. doi
  8. Evidence for a gene influencing blood pressure on chromosome 17: genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study. doi
  9. (2004). Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol. doi
  10. Genetic determinants of hypertension: identification of candidate phenotypes. doi
  11. (1999). Genetic variance components analysis for binary phenotypes using generalized linear mixed models (GLMMs) and Gibbs sampling. Genet Epidemiol. doi
  12. (2005). Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension (BRIGHT) study. Hum Mol Genet. doi
  13. Human hypertension caused by mutations in WNK kinases.
  14. Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. doi
  15. (1998). Improved hypertension management and control: results from the health survey for England doi
  16. (2005). LINkage disequilibrium plotter. Available at http:// www.genepi.com.au/jlin; last accessed
  17. Mendelian randomisation’: can genetic epidemiology contribute to understanding environmental determinants of disease? doi
  18. Molecular mechanisms of human hypertension. doi
  19. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. doi
  20. (1998). PedCheck: a program for identification of genotype incompatibilities in linkage analysis. doi
  21. Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density. doi
  22. Sibling-based tests of linkage and association for quantitative traits. doi
  23. Surveys Unit. Health Survey for England 2003. Volume 2: Risk Factors for Cardiovascular Disease. London: The Stationery Office;
  24. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. doi
  25. WNK4 intron 10 polymorphism is not associated with hypertension. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.