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


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.

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The authors gratefully acknowledge the use of laboratory facilities of the Research Center for High Altitude Medicine at Qinghai University, Xining, China; the Regional Center for Biotechnology, Government of India, Gurgaon, India; and the Tibet Institute of Medical Sciences, Lhasa, Tibet Autonomous Region, China.

TB was supported by project “Increasing Opportunities for Career Growth in Research and Development in the Field of Medical Sciences,” ITMS: 26110230067. Ge RiLi is supported by National Basic Research Program (NBRP# 2012CB518200, PIS&T # 0S2012GR0195) and National Natural Science Foundation of China (# 30393133). JP is supported by NIH-P01CA108671, VA Merit Review Award and University of Utah Seed Grant Program for studies of hypoxic adaptation. The Colorado cohort study materials were made possible by NSF BNS-8919645 and DAMD 17-87-C-7202 grants to Lorna G. Moore.

We thank Robert Pryor for developing the double-layer capillary tube method used to genotype EGLN1 c.12C>G.

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Corresponding authors

Correspondence to Josef T. Prchal or RiLi Ge.

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Written informed consent was obtained from all participants and institutional review board approval by each collaborating group was also obtained.

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The authors declare that they have no conflict of interest to declare.

Additional information

Victor R. Gordeuk, Josef T. Prchal, and RiLi Ge contributed equally to this work.

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Tashi, T., Scott Reading, N., Wuren, T. et al. Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders. J Mol Med 95, 665–670 (2017).

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  • High altitude
  • Genetic adaptation
  • Polycythemia
  • Hypoxia
  • High-resolution melting assay