title: Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia.
abstract: Tibetan natives have lived on the Tibetan plateau (altitude ∼ 4,000 m) for at least 25,000 years, and as such they are adapted to life and reproduction in a hypoxic environment. Recent studies have identified two genetic loci, EGLN1 and EPAS1, that have undergone natural selection in Tibetans, and further demonstrated an association of EGLN1/EPAS1 genotype with hemoglobin concentration. Both genes encode major components of the hypoxia-inducible factor (HIF) transcriptional pathway, which coordinates an organism's response to hypoxia. Patients living at sea level with genetic disease of the HIF pathway have characteristic phenotypes at both the integrative-physiology and cellular level. We sought to test the hypothesis that natural selection to hypoxia within Tibetans results in related phenotypic differences. We compared Tibetans living at sea level with Han Chinese, who are Tibetans' most closely related major ethnic group. We found that Tibetans had a lower hemoglobin concentration, a higher pulmonary ventilation relative to metabolism, and blunted pulmonary vascular responses to both acute (minutes) and sustained (8 h) hypoxia. At the cellular level, the relative expression and hypoxic induction of HIF-regulated genes were significantly lower in peripheral blood lymphocytes from Tibetans compared with Han Chinese. Within the Tibetans, we found a significant correlation between both EPAS1 and EGLN1 genotype and the induction of erythropoietin by hypoxia. In conclusion, this study provides further evidence that Tibetans respond less vigorously to hypoxic challenge. This is evident at sea level and, at least in part, appears to arise from a hyporesponsive HIF transcriptional system.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
authors.forename: Nayia
authors.initials: N
authors.lastname: Petousi
authors.forename: Quentin P P
authors.initials: QP
authors.lastname: Croft
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
authors.forename: Hung-Yuan
authors.initials: HY
authors.lastname: Cheng
authors.forename: Federico
authors.initials: F
authors.lastname: Formenti
authors.forename: Koji
authors.initials: K
authors.lastname: Ishida
authors.forename: Daniel
authors.initials: D
authors.lastname: Lunn
authors.forename: Mark
authors.initials: M
authors.lastname: McCormack
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Nick P
authors.initials: NP
authors.lastname: Talbot
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robbins
mesh_terms: D000064:Acclimatization / Q000235:genetics; D000328:Adult; D000531:Altitude; D044466:Asian People / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002681:China / Q000453:epidemiology; D004921:Erythropoietin / Q000097:blood; D005786:Gene Expression Regulation; D006239:Haplotypes; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000097:blood; D010641:Phenotype; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D012123:Pulmonary Ventilation; D012641:Selection, Genetic; D018609:Tibet / Q000453:epidemiology; D013997:Time Factors; D014158:Transcription, Genetic; D014661:Vasoconstriction; D055815:Young Adult; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D006454:Hemoglobins; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen; D000099162:Endothelial PAS Domain-Containing Protein 1; C554270:EPO protein, human; C490190:EGLN1 protein, human
keywords: EGLN1; EPAS1; erythropoietin; high altitude; hypoxic pulmonary vasoconstriction
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