Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans

Margus Putku (1) , Katrin Kepp (1) , Elin Org (1) , Siim Sõber (1) , David Comas (2) , Margus Viigimaa (3) , Gudrun Veldre (1, 4) , Peeter Juhanson (1) , Pille Hallast (1) , Neeme Tõnisson (1) , Sue Shaw-Hawkins (5) , Mark J Caulfield (1) , Elza Khusnutdinova (6) , Viktor Kožich (7) , Patricia B. Munroe (1) , Maris Laan (8)

1 Institute of Molecular and Cell Biology
2 Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB
3 Centre of Cardiology
4 Department of Cardiology
5 Clinical Pharmacology and The Genome Centre
6 Institute of Biochemistry and Genetics of Ufa Scientific Centre
7 Institute of Inherited Metabolic Disorders
8 Institute of Molecular and Cell Biology

Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon syndrome. WNK1 and WNK4 conserved non-coding 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% versus 15.8%; P=9.7x10-9). Meta-analysis across three European sample-sets (n=3494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P=4.03x10-3, effect 1.12; diastolic BP, P=1.21x10-2, effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n=2088; SBP, P=1.99x10-3, effect 1.59; DBP P=3.64x10-4, effect 1.23; resistant to Bonferroni correction), while no statistical support was identified for the association with male BP (n=1406). 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 non-carriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts.

Mots clés: Life Sciences

Margus Putku, Katrin Kepp, Elin Org, Siim Sõber, David Comas, et al.. Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans. Human Mutation, 2011, 32 (7), pp.806. ⟨10.1002/humu.21508⟩. ⟨hal-00639773⟩