title: Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans.
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.
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Margus
authors.initials: M
authors.lastname: Putku
authors.forename: Katrin
authors.initials: K
authors.lastname: Kepp
authors.forename: Elin
authors.initials: E
authors.lastname: Org
authors.forename: Siim
authors.initials: S
authors.lastname: Sõber
authors.forename: David
authors.initials: D
authors.lastname: Comas
authors.forename: Margus
authors.initials: M
authors.lastname: Viigimaa
authors.forename: Gudrun
authors.initials: G
authors.lastname: Veldre
authors.forename: Peeter
authors.initials: P
authors.lastname: Juhanson
authors.forename: Pille
authors.initials: P
authors.lastname: Hallast
authors.forename: Neeme
authors.initials: N
authors.lastname: Tõnisson
authors.forename: Sue
authors.initials: S
authors.lastname: Shaw-Hawkins
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: Elza
authors.initials: E
authors.lastname: Khusnutdinova
authors.forename: Viktor
authors.initials: V
authors.lastname: Kožich
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.forename: Maris
authors.initials: M
authors.lastname: Laan
mesh_terms: D000328:Adult; D000349:Africa; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics; D020087:Alu Elements / Q000235:genetics*; D001176:Arthrogryposis / Q000235:genetics*; D001208:Asia; D001794:Blood Pressure / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D003025:Clubfoot / Q000235:genetics*; D005060:Europe; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D016254:Mutagenesis, Insertional; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human