Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia

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 fu...

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Main Authors:	Petousi, Nayia, Croft, Quentin P. P., Cavalleri, Gianpiero L., Cheng, Hung-Yuan, Formenti, Federico, Ishida, Koji, Lunn, Daniel, McCormack, Mark, Shianna, Kevin V., Talbot, Nick P., Ratcliffe, Peter J., Robbins, Peter A.
Format:	Online
Language:	English
Published:	American Physiological Society 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972739/

id	pubmed-3972739
recordtype	oai_dc
spelling	pubmed-39727392014-08-05 Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia Petousi, Nayia Croft, Quentin P. P. Cavalleri, Gianpiero L. Cheng, Hung-Yuan Formenti, Federico Ishida, Koji Lunn, Daniel McCormack, Mark Shianna, Kevin V. Talbot, Nick P. Ratcliffe, Peter J. Robbins, Peter A. Highlighted Topic 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. American Physiological Society 2013-09-12 2014-04-01 /pmc/articles/PMC3972739/ /pubmed/24030663 http://dx.doi.org/10.1152/japplphysiol.00535.2013 Text en Copyright © 2014 the American Physiological Society Licensed under Creative Commons Attribution CC-BY 3.0 (http://creativecommons.org/licenses/by/3.0/deed.en_US) : the American Physiological Society.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Petousi, Nayia Croft, Quentin P. P. Cavalleri, Gianpiero L. Cheng, Hung-Yuan Formenti, Federico Ishida, Koji Lunn, Daniel McCormack, Mark Shianna, Kevin V. Talbot, Nick P. Ratcliffe, Peter J. Robbins, Peter A.
spellingShingle	Petousi, Nayia Croft, Quentin P. P. Cavalleri, Gianpiero L. Cheng, Hung-Yuan Formenti, Federico Ishida, Koji Lunn, Daniel McCormack, Mark Shianna, Kevin V. Talbot, Nick P. Ratcliffe, Peter J. Robbins, Peter A. Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia
author_facet	Petousi, Nayia Croft, Quentin P. P. Cavalleri, Gianpiero L. Cheng, Hung-Yuan Formenti, Federico Ishida, Koji Lunn, Daniel McCormack, Mark Shianna, Kevin V. Talbot, Nick P. Ratcliffe, Peter J. Robbins, Peter A.
author_sort	Petousi, Nayia
title	Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia
title_short	Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia
title_full	Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia
title_fullStr	Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia
title_full_unstemmed	Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia
title_sort	tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia
description	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.
publisher	American Physiological Society
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972739/
_version_	1612073182198497280

Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia

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