STK39 and WNK1 Are Potential Hypertension Susceptibility Genes in the BELHYPGEN Cohort

Abstract

The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na+/Cl− cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension.Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms—rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)—using the Snapshot method.The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2–15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5–11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02).Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted.

Association of with‐no‐lysine kinase 1 and Serine/Threonine kinase 39 gene polymorphisms and haplotypes with essential hypertension in Tibetans

“…No significant connections between other sites and EH were found in our study, which is in accordance with some previous reports while inconsistent with others [Newhouse et al, ; Persu et al, ; Yang et al, ]. These inconsistent results may be due to the fact that most studies have focused on the single‐locus effect and disregarded epistasis, so haplotypes and WNK1‐STK39 interaction were performed in this study to overcome this drawback.…”

An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort

“…Flanking CpGs on the 450K array (cg21899461 and cg03331300) were also associated with BMI at p<0.05. Polymorphisms in this gene have been linked to risk of hypertension (33-35). Epigenetic silencing of STK39 through DNA hypermethylation in B-cell lymphoma appears to promote cancer progression by inhibiting apoptosis in cells with DNA damage (36).…”

A meta-analytical assessment of STK39 three well-defined polymorphisms in susceptibility to hypertension

“…Since serine/threonine kinase 39 gene ( STK39 ) was first identified as a hypertension-susceptibility gene by a genome-wide association study in 2009 1 , it has become a major target of ongoing studies to unravel which genetic loci in STK39 can predispose individuals at risk for elevated blood pressure 2 3 4 . Biologically, STK39 gene encodes a serine/threnine kinase termed as a Ste20-related proline/alanine-rich kinase (SPAK).…”