title: 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.
authors.affiliation: From the Pole of Cardiovascular Research (AP, LE, SH), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; Cardiology Department (AP, GN), Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium; Human Molecular Genetics (LE, AM, MV), de Duve Institute, Université catholique de Louvain, Brussels, Belgium; Studies Coordinating Centre (YJ, W-YY, JAS), Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; Population Health and Optimal Health Practices Research Unit (GN), CHU de Québec Research Centre, Québec, Canada; Pôle de recherche en Endocrinologie (DG), Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium; Department of Laboratory Medicine (DG), Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium; and Research and Development VitaK Group (JAS), Maastricht University, Maastricht, The Netherlands.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Persu
authors.forename: Lucie
authors.initials: L
authors.lastname: Evenepoel
authors.forename: Yu
authors.initials: Y
authors.lastname: Jin
authors.forename: Antonella
authors.initials: A
authors.lastname: Mendola
authors.forename: Gérard
authors.initials: G
authors.lastname: Ngueta
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Yang
authors.forename: Damien
authors.initials: D
authors.lastname: Gruson
authors.forename: Sandrine
authors.initials: S
authors.lastname: Horman
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
mesh_terms: D000328:Adult; D000368:Aged; D001530:Belgium; D001794:Blood Pressure; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D044465:White People
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human