TY - JOUR
T1 - Polymorphisms in the WNK1 gene are asociated with blood pressure variation and urinary potassium excretion
AU - Newhouse, Stephen
AU - Farrall, Martin
AU - Wallace, Chris
AU - Hoti, Mimoza
AU - Burke, Beverley
AU - Howard, Philip
AU - Onipinla, Abiodun
AU - Lee, Kate
AU - Shaw-Hawkins, Sue
AU - Dobson, Richard
AU - Brown, Morris
AU - Samani, Nilesh J.
AU - Dominiczak, Anna F.
AU - Connell, John M.
AU - Lathrop, G. Mark
AU - Kooner, Jaspal
AU - Chambers, John
AU - Elliott, Paul
AU - Clarke, Robert
AU - Collins, Rory
AU - Laan, Maris
AU - Org, Elin
AU - Juhanson, Peeter
AU - Veldre, Gudrun
AU - Viigimaa, Margus
AU - Eyheramendy, Susana
AU - Cappucio, Francesco P.
AU - Ji, Chen
AU - Iacone, Roberto
AU - Strazzullo, Pasquale
AU - Kumari, Meena
AU - Marmot, Michael
AU - Brunner, Eric
AU - Caulfield, Mark
AU - Munroe, Patricia B.
PY - 2009/4/4
Y1 - 2009/4/4
N2 - 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 × 10-3, combined with BRIGHT data-set p = 2 × 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.
AB - 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 × 10-3, combined with BRIGHT data-set p = 2 × 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.
UR - http://www.scopus.com/inward/record.url?scp=64549097211&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0005003
DO - 10.1371/journal.pone.0005003
M3 - Article
C2 - 19347040
AN - SCOPUS:64549097211
SN - 1932-6203
VL - 4
JO - PLoS ONE
JF - PLoS ONE
IS - 4
M1 - e5003
ER -