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

Abstract

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.

Regulation of WNK1 Expression by miR-192 and Aldosterone

“…The polymorphism rs11571461 was found at a frequency similar to that previously described in Caucasian subjects. 40 However, this polymorphism described downstream of WNK1 is actually located in the RAD52 gene.…”

The WNK Kinase Network Regulating Sodium, Potassium, and Blood Pressure

“…65,79 Indeed, several population studies now identify single nucleotide polymorphisms and haploptypes in the WNK1 and WNK4 genes that are not only associated with BP variation 80 but also with hypertension severity, 81 salt sensitivity, 82 thiazide sensitivity, 83 and urine potassium excretion. 84 Interestingly, the WNK1 and WNK4 single nucleotide polymorphisms with the strongest associations were either located in or near the sites of the FHHt mutations. 84,85 Although the effects of variants in a single gene may be modest, one study showed that when variants in the genes for WNK1, ␣-adducin (a cytoskeleton protein that also influences Na ϩ -K ϩ -ATPase activity), and Nedd4 -2 (which ubiquinates ENaC) were combined, a significant effect was found on renal salt handling, the BP response to saline and thiazides, and nocturnal systolic BP.…”

Advances in Blood Pressure Genomics

“…There are some data suggesting that rare haplotypes of WNK1 and common variants at the inwardly rectifying potassium channel ROMK may have modest effects on blood pressure. [26][27][28][29][30] In the Framingham Heart Study, the effect of rare variants in the SLC12A3 (NCC), SLC12A1 (NKCC2), and the inwardly rectifying potassium channel, KCNJ1 (ROMK), genes were tested for to see if they influence blood pressure. 31 These genes cause rare recessive disorders with substantial effects on blood pressure (≈6-10 mm Hg systolic).…”