Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population.
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.


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.
Tobin
Martin D
MD
Department of Health Sciences, University of Leicester, Leicester, England.
Raleigh
Stuart M
SM
Newhouse
Stephen
S
Braund
Peter
P
Bodycote
Clare
C
Ogleby
Jenny
J
Cross
Deborah
D
Gracey
Jay
J
Hayes
Saija
S
Smith
Terry
T
Ridge
Cathy
C
Caulfield
Mark
M
Sheehan
Nuala A
NA
Munroe
Patricia B
PB
Burton
Paul R
PR
Samani
Nilesh J
NJ
D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000235:genetics; D018660:Blood Pressure Monitoring, Ambulatory; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics / Q000401:mortality; D005060:Europe; D005192:Family Health; D005247:Feeding Behavior; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D017720:Molecular Epidemiology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000076204:WNK Lysine-Deficient Protein Kinase 1
D000959:Antihypertensive Agents; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human