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: Margus Putku, Katrin Kepp, Elin Org, Siim Sõber, David Comas, Margus Viigimaa, Gudrun Veldre, Peeter Juhanson, Pille Hallast, Neeme Tõnisson, HYPertension in ESTonia (HYPEST), Sue Shaw-Hawkins, Mark J Caulfield, BRItish Genetics of HyperTension (BRIGHT), Elza Khusnutdinova, Viktor Kožich, Patricia B Munroe, Maris Laan
• Journal: Human mutation (Hum Mutat) Vol. 32 Issue 7 Pg. 806-14 (Jul 2011) ISSN: 1098-1004 [Electronic] United States
• PMID: 21520334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Wiley-Liss, Inc.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Minor Histocompatibility Antigens
• Protein Serine-Threonine Kinases
• WNK Lysine-Deficient Protein Kinase 1
• WNK1 protein, human

Topics

• Adult
• Africa
• Aged
• Alternative Splicing (genetics)
• Alu Elements (genetics)
• Arthrogryposis (genetics)
• Asia
• Blood Pressure (genetics)
• Cleft Palate (genetics)
• Clubfoot (genetics)
• Europe
• Exons
• Female
• Genetic Variation
• Hand Deformities, Congenital (genetics)
• Humans
• Hypertension (genetics)
• Intracellular Signaling Peptides and Proteins
• Introns
• Male
• Middle Aged
• Minor Histocompatibility Antigens
• Mutagenesis, Insertional
• Polymorphism, Genetic
• Protein Serine-Threonine Kinases (genetics)
• WNK Lysine-Deficient Protein Kinase 1
• White People (genetics)
• Young Adult