Abstract
Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon syndrome. WNK1 and WNK4 conserved noncoding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia, and Africa (n = 854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out of Africa. The allele frequency in Sub-Saharan Africa was ∼3.3 times lower than in other populations (4.8 vs. 15.8%; P = 9.7 × 10−9). Meta-analysis across three European sample sets (n = 3,494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P = 4.03 × 10−3, effect 1.12; diastolic BP, P = 1.21 × 10−2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n = 2,088; SBP, P = 1.99 × 10−3, effect 1.59; DBP P = 3.64 × 10−4, effect 1.23; resistant to Bonferroni correction), whereas no statistical support was identified for the association with male BP (n = 1,406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to noncarriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc.
Highlights
Essential hypertension is a complex disease promoted by an unfavorable combination of person’s life style and heritable factors
Denaturing High-Performance Liquid Chromatography method (DHPLC) and/or Denaturing Gradient Gel Electrophoresis (DGGE) assays were designed for screening novel polymorphisms in Conserved noncoding regions (CNRs) of the WNK1 (29 targeted CNRs based on criteria outlined in Materials and Methods) and the WNK4 (11 CNRs) genes
We targeted conserved noncoding regions in hypertension candidate genes WNK1 and WNK4 to polymorphism screening in order to identify functional variants potentially contributing to blood pressure (BP) determination
Summary
Essential hypertension is a complex disease promoted by an unfavorable combination of person’s life style and heritable factors. It is a significant health risk leading to other cardiovascular and renal diseases. Mendelian forms of hypo- and hypertension have identified $20 rare mutations in blood pressure regulating genes with a strong effect on the phenotype [Lifton et al, 2001; Vehaskari, 2007]. These rare mutations do not explain blood pressure variation in the general population, the identified genes are promising targets for functional, physiological and genetic studies of essential hypertension [Ji et al, 2008]. WNK1 and WNK4 are expressed in multiple tissues, their major role is to regulate the transport of sodium and potassium ions in
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