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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.

Polymorphisms in the WNK1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion