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 = 761023
, combined
with BRIGHT data-set p = 261024
, 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,1027
). 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.