Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders

  • Tsewang Tashi
  • N. Scott Reading
  • Tanna Wuren
  • Xu Zhang
  • Lorna G. Moore
  • Hao Hu
  • Feng Tang
  • Anna Shestakova
  • Felipe Lorenzo
  • Tatiana Burjanivova
  • Parvaiz Koul
  • Prasenjit Guchhait
  • Carl T. Wittwer
  • Colleen G. Julian
  • Binal Shah
  • Chad D. Huff
  • Victor R. Gordeuk
  • Josef T. Prchal
  • RiLi Ge
Original Article

DOI: 10.1007/s00109-017-1519-3

Cite this article as:
Tashi, T., Scott Reading, N., Wuren, T. et al. J Mol Med (2017). doi:10.1007/s00109-017-1519-3
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Abstract

Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans.

Key message

  • Most Tibetans are protected from polycythemia while living in high altitude.

  • An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan.

  • The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome.

  • While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.

Keywords

High altitude Genetic adaptation Polycythemia Hypoxia High-resolution melting assay 

Supplementary material

109_2017_1519_MOESM1_ESM.pdf (841 kb)
ESM 1(PDF 841 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Tsewang Tashi
    • 1
  • N. Scott Reading
    • 1
    • 2
  • Tanna Wuren
    • 3
  • Xu Zhang
    • 4
  • Lorna G. Moore
    • 5
  • Hao Hu
    • 6
  • Feng Tang
    • 3
  • Anna Shestakova
    • 2
  • Felipe Lorenzo
    • 1
  • Tatiana Burjanivova
    • 1
    • 7
  • Parvaiz Koul
    • 8
  • Prasenjit Guchhait
    • 9
  • Carl T. Wittwer
    • 2
  • Colleen G. Julian
    • 5
  • Binal Shah
    • 4
  • Chad D. Huff
    • 6
  • Victor R. Gordeuk
    • 4
  • Josef T. Prchal
    • 1
    • 2
    • 10
    • 11
  • RiLi Ge
    • 3
  1. 1.Division of HematologyUniversity of UtahSalt Lake CityUSA
  2. 2.Department of Pathology and ARUP LaboratoriesUniversity of UtahSalt Lake CityUSA
  3. 3.Research Center for High-Altitude MedicineQinghai UniversityXiningChina
  4. 4.Division of Hematology and Oncology, Department of MedicineUniversity of Illinois at ChicagoChicagoUSA
  5. 5.Departments of Medicine and Obstetrics/GynecologyUniversity of Colorado DenverAuroraUSA
  6. 6.MD Anderson Cancer CenterUniversity of TexasHoustonUSA
  7. 7.Department of Molecular Biology, Jessenius Faculty of Medicine in MartinComenius University in BratislavaBratislavaSlovakia
  8. 8.Sher-i-Kashmir Institute of Medical SciencesSrinagarIndia
  9. 9.Regional Centre for BiotechnologyFaridabadIndia
  10. 10.Department of Pathophysiology and 1st Department of Medicine, 1st Faculty MedicineCharles University in PraguePragueCzech Republic
  11. 11.Hematology, SOM 5C310University of Utah School of MedicineSalt Lake CityUSA

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