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

  1. Margus Putku1,
  2. Katrin Kepp1,
  3. Elin Org1,
  4. Siim Sõber1,
  5. David Comas2,
  6. Margus Viigimaa3,4,
  7. Gudrun Veldre1,5,
  8. Peeter Juhanson1,
  9. Pille Hallast1,
  10. Neeme Tõnisson1,
  11. HYPEST‡,
  12. Sue Shaw-Hawkins6,
  13. Mark J. Caulfield6,
  14. BRIGHT‡,
  15. Elza Khusnutdinova7,
  16. Viktor Kožich8,
  17. Patricia B. Munroe6,
  18. Maris Laan1,*

Article first published online: 10 MAY 2011

DOI: 10.1002/humu.21508

Issue

Human Mutation

Human Mutation

Volume 32, Issue 7, pages 806–814, July 2011

Additional Information

How to Cite

Putku, M., Kepp, K., Org, E., Sõber, S., Comas, D., Viigimaa, M., Veldre, G., Juhanson, P., Hallast, P., Tõnisson, N., HYPEST, Shaw-Hawkins, S., Caulfield, M. J., BRIGHT, Khusnutdinova, E., Kožich, V., Munroe, P. B. and Laan, M. (2011), Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans. Human Mutation, 32: 806–814. doi: 10.1002/humu.21508

Author Information

  1. 1

    Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia

  2. 2

    Institute of Evolutionary Biology (UPF-CSIC), CEXS-UPF-PRBB, Universitat Pompeu Fabra, Barcelona, Spain

  3. 3

    Centre of Cardiology, North Estonia Medical Centre, Tallinn, Estonia

  4. 4

    Tallinn University of Technology, Department of Biomedical Engineering, Chair of Medical Physics, Tallinn, Estonia

  5. 5

    Department of Cardiology, University of Tartu, Tartu, Estonia

  6. 6

    Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom

  7. 7

    Institute of Biochemistry and Genetics, Ufa Science Center, Russian Academy of Sciences, Ufa, Bashkortostan, Russia

  8. 8

    Institute of Inherited Metabolic Diseases, Charles University—First Faculty of Medicine, Prague, Czech Republic

  1. ‡

    HYPertension in ESTonia (HYPEST), the British Genetics of Hypertension (BRIGHT); additional BRIGHT consortium members are given in Supp. Text S1.

*Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia

  1. †

    Communicated by Pui-Yan Kwok

Publication History

  1. Issue published online: 27 JUN 2011
  2. Article first published online: 10 MAY 2011
  3. Accepted manuscript online: 21 APR 2011 01:28PM EST
  4. Manuscript Accepted: 28 MAR 2011
  5. Manuscript Received: 6 DEC 2010

Funded by

  • Wellcome Trust International Senior Research Fellowships. Grant Numbers: 070191/Z/03/Z (to M.L.), 070255/Z/03/Z (to V.K.) in Biomedical Science in Central Europe
  • The BRIGHT study was supported by the Medical Research Council of Great Britain. Grant Number: G9521010D
  • British Heart Foundation. Grant Number: PG02/128
  • The Barts and The London Charity
  • The HYPEST study was supported by the Estonian Ministry of Education and Science. Grant Number: 0182721s06
  • HHMI International Scholarship. Grant Number: 55005617 (to M.L.)
  • Estonian Science Foundation. Grant Number: ETF7471 (to M.L.; stipend for M.P.)
  • The CADCZ study was supported by the Ministry of Health of the Czech Republic. Grant Number: NS10036-4/2008 (to V.K.)

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Keywords:

  • WNK1;
  • polymorphism screening;
  • AluYb8;
  • blood pressure;
  • meta-analysis

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.

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