Polymorphisms in the WNK1 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 = 7 x 10(-3), combined with BRIGHT data-set p = 2 x 10(-4), 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(-7)). 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.
Clinical Pharmacology and Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
Stephen
S
Newhouse
Martin
M
Farrall
Chris
C
Wallace
Mimoza
M
Hoti
Beverley
B
Burke
Philip
P
Howard
Abiodun
A
Onipinla
Kate
K
Lee
Sue
S
Shaw-Hawkins
Richard
R
Dobson
Morris
M
Brown
Nilesh J
NJ
Samani
Anna F
AF
Dominiczak
John M
JM
Connell
G Mark
GM
Lathrop
Jaspal
J
Kooner
John
J
Chambers
Paul
P
Elliott
Robert
R
Clarke
Rory
R
Collins
Maris
M
Laan
Elin
E
Org
Peeter
P
Juhanson
Gudrun
G
Veldre
Margus
M
Viigimaa
Susana
S
Eyheramendy
Francesco P
FP
Cappuccio
Chen
C
Ji
Roberto
R
Iacone
Pasquale
P
Strazzullo
Meena
M
Kumari
Michael
M
Marmot
Eric
E
Brunner
Mark
M
Caulfield
Patricia B
PB
Munroe
D000328:Adult; D001794:Blood Pressure / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000652:urine*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000076204:WNK Lysine-Deficient Protein Kinase 1
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; D011188:Potassium