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

2014 ◽  
Vol 116 (7) ◽  
pp. 893-904 ◽  
Author(s):  
Nayia Petousi ◽  
Quentin P. P. Croft ◽  
Gianpiero L. Cavalleri ◽  
Hung-Yuan Cheng ◽  
Federico Formenti ◽  
...  
Keyword(s):  
Natural Selection ◽  
Sea Level ◽  
Pulmonary Ventilation ◽  
Hypoxia Inducible Factor ◽  
Hemoglobin Concentration ◽  
Peripheral Blood Lymphocytes ◽  
Cellular Level ◽  
Han Chinese ◽  
The Tibetan Plateau ◽  
Integrative Physiology

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.

scholarly journals Human adaptation to the hypoxia of high altitude: the Tibetan paradigm from the pregenomic to the postgenomic era

2014 ◽  
Vol 116 (7) ◽  
pp. 875-884 ◽  
Author(s):  
Nayia Petousi ◽  
Peter A. Robbins
Keyword(s):  
Natural Selection ◽  
High Altitude ◽  
Hypoxia Inducible Factor ◽  
Hemoglobin Concentration ◽  
Phenotypic Traits ◽  
The Tibetan Plateau ◽  
Oxygen Homeostasis ◽  
Functional Variants ◽  
Hypoxic Environment ◽  
Underlying Mechanisms

The Tibetan Plateau is one of the highest regions on Earth. Tibetan highlanders are adapted to life and reproduction in a hypoxic environment and possess a suite of distinctive physiological traits. Recent studies have identified genomic loci that have undergone natural selection in Tibetans. Two of these loci, EGLN1 and EPAS1, encode major components of the hypoxia-inducible factor transcriptional system, which has a central role in oxygen sensing and coordinating an organism's response to hypoxia, as evidenced by studies in humans and mice. An association between genetic variants within these genes and hemoglobin concentration in Tibetans at high altitude was demonstrated in some of the studies ( 8 , 80 , 96 ). Nevertheless, the functional variants within these genes and the underlying mechanisms of action are still not known. Furthermore, there are a number of other possible phenotypic traits, besides hemoglobin concentration, upon which natural selection may have acted. Integration of studies at the genomic level with functional molecular studies and studies in systems physiology has the potential to provide further understanding of human evolution in response to high-altitude hypoxia. The Tibetan paradigm provides further insight on the role of the hypoxia-inducible factor system in humans in relation to oxygen homeostasis.

scholarly journals Variations within oxygen-regulated gene expression in humans

2009 ◽  
Vol 106 (1) ◽  
pp. 212-220 ◽  
Author(s):  
Jerome T. S. Brooks ◽  
Gareth P. Elvidge ◽  
Louisa Glenny ◽  
Jonathan M. Gleadle ◽  
Chun Liu ◽  
...  
Keyword(s):  
Cellular Response ◽  
Genetic Manipulation ◽  
Hypoxia Inducible Factor ◽  
Hereditary Disease ◽  
Peripheral Blood Lymphocytes ◽  
Cellular Level ◽  
Normal Individuals ◽  
Regulated Gene Expression ◽  
Open Question ◽  
Hif Pathway

The effects of hypoxia on gene transcription are mainly mediated by a transcription factor complex termed hypoxia-inducible factor (HIF). Genetic manipulation of animals and studies of humans with rare hereditary disease have shown that modifying the HIF pathway affects systems-level physiological responses to hypoxia. It is, however, an open question whether variations in systems-level responses to hypoxia between individuals could arise from variations within the HIF system. This study sought to determine whether variations in the responsiveness of the HIF system at the cellular level could be detected between normal individuals. Peripheral blood lymphocytes (PBL) were isolated on three separate occasions from each of 10 healthy volunteers. After exposure of PBL to eight different oxygen tensions ranging from 20% to 0.1%, the expression levels of four HIF-regulated transcripts involved in different biological pathways were measured. The profile of expression of all four transcripts in PBL was related to oxygen tension in a curvilinear manner. Double logarithmic transformation of these data resulted in a linear relationship that allowed the response to be parameterized through a gradient and intercept. Analysis of variance (ANOVA) on these parameters showed that the level of between-subject variation in the gradients of the responses that was common across all four HIF-regulated transcripts was significant ( P = 0.008). We conclude that statistically significant variation within the cellular response to hypoxia can be detected between normal humans. The common nature of the variability across all four HIF-regulated genes suggests that the source of this variation resides within the HIF system itself.

scholarly journals Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude

2019 ◽  
Vol 116 (48) ◽  
pp. 24006-24011 ◽  
Author(s):  
Tom D. Brutsaert ◽  
Melisa Kiyamu ◽  
Gianpietro Elias Revollendo ◽  
Jenna L. Isherwood ◽  
Frank S. Lee ◽  
...  
Keyword(s):  
Natural Selection ◽  
Aerobic Capacity ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Total Sample ◽  
Causal Variant ◽  
Analysis Of Covariance ◽  
Adaptation To Hypoxia ◽  
Spurious Association ◽  
Factor Α

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (L⋅min−1 and mL⋅min−1⋅kg−1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min−1⋅kg−1 vs. CC = 30.5 mL⋅min−1⋅kg−1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.

scholarly journals Condensing Life Substances within the House: The Rice-Boiling Shuhi of Southwest China

2017 ◽  
Vol 71 (1) ◽  
Author(s):  
Elisabeth Hsu ◽  
Franz K. Huber ◽  
Caroline S. Weckerle
Keyword(s):  
Tibetan Plateau ◽  
Southeast Asia ◽  
High Altitude ◽  
Sea Level ◽  
Ethnic Groups ◽  
Southwest China ◽  
Cultural Practice ◽  
The Tibetan Plateau ◽  
Regional Culture ◽  
Fault Line

AbstractThe Shuhi of Muli County, Sichuan Province, are one of multiple ethnic groups inhabiting the river gorges of the Qinghai-Gansu-Sichuan corridor between the Tibetan plateau and the Chinese lowlands. The Shuhi have grown paddy rice since times immemorial at an unusually high altitude (ca. 2,300 m above sea level). This article aims to explain this conundrum not merely through the ecology (as is common among Tibetan area specialists), but by researching the cultivation and consumption of rice as a historically-evolved cultural practice. According to a recently formulated agro-archaeological hypothesis regarding the macro-region of Eurasia, it is possible to identify two supra-regional culture complexes distinguished by their respective culinary technologies: rice-boiling versus wheat-grinding-and-baking. The hypothesis posits that the fault line between the two supra-regional cultural complexes is precisely along this river gorges corridor. In this article we provide support for this hypothesis arguing that Shuhi ritual and kinship practices have much affinity with those of other rice-boiling peoples in Southeast Asia, whereas certain of their current religious practices are shared with the wheat-grinding Tibetans.

The Influence of Altitude on Erythropoietin Resistance Index in Maintenance Hemodialysis Patients: Data from Tibetan Plateau

2020 ◽  
pp. 1-6
Author(s):  
Yan Wang ◽  
Zong-hui Dang ◽  
Liang-ying Gan ◽  
Ciren Luobu ◽  
Lei Zhang ◽  
...  
Keyword(s):  
High Altitude ◽  
Sea Level ◽  
Resistance Index ◽  
Hemoglobin Concentration ◽  
Maintenance Hemodialysis ◽  
Autonomous Region ◽  
Tibet Autonomous Region ◽  
Dialysis Vintage ◽  
Peking University ◽  
The Impact

Background: It is known that hypoxia influences many of the biologic processes involved in erythropoiesis; therefore, the high-altitude hypoxia may affect erythropoietin (EPO) responsiveness in maintenance hemodialysis (MHD) patients. This study aimed to evaluate the impact of altitude on EPO responsiveness in MHD patients. Methods: In this retrospective study, MHD patients from Tibet Autonomous Region People’s Hospital (3,650 m above sea level) and Peking University People’s Hospital (43.5 m above sea level) were recruited between May 2016 and December 2018. Patients were divided into 2 groups according to altitude. Variables including age, sex, dialysis vintage, dialysis modality, duration of EPO use, EPO doses, and laboratory tests were collected and analyzed. EPO responsiveness was measured in terms of the EPO resistance index (ERI). ERI was defined as the weekly weight-adjusted dose of EPO (IU/kg/week) divided by hemoglobin concentration (g/dL). The association between ERI and altitude was estimated using a multivariable linear regression model. Results: Sixty-two patients from Tibet Autonomous Region People’s Hospital (high-altitude [HA] group) and 102 patients from Peking University People’s Hospital (low-altitude [LA] group) were recruited. The ERI for HA group and LA group was 6.9 ± 5.1 IU w−1 kg−1 (g/dL)−1 and 11.5 ± 6.4 IU w−1 kg−1 (g/dL)−1, respectively. After adjusting for covariates by multivariable regression, altitude was independently associated with ERI (R2 = 0.245, p < 0.001). Conclusion: Altitude had an independent negative correlation with ERI. This result supported the hypothesis that altitude-associated hypoxia improved EPO responsiveness in MHD patients.

Oxygen transport to exercising leg in chronic hypoxia

1988 ◽  
Vol 65 (6) ◽  
pp. 2592-2597 ◽  
Author(s):  
P. R. Bender ◽  
B. M. Groves ◽  
R. E. McCullough ◽  
R. G. McCullough ◽  
S. Y. Huang ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sea Level ◽  
Chronic Hypoxia ◽  
Peripheral Resistance ◽  
Hemoglobin Concentration ◽  
Barometric Pressure ◽  
Ambient Air ◽  
Leg Blood Flow ◽  
State Cycle ◽  
O2 Delivery

Residence at high altitude could be accompanied by adaptations that alter the mechanisms of O2 delivery to exercising muscle. Seven sea level resident males, aged 22 +/- 1 yr, performed moderate to near-maximal steady-state cycle exercise at sea level in normoxia [inspired PO2 (PIO2) 150 Torr] and acute hypobaric hypoxia (barometric pressure, 445 Torr; PIO2, 83 Torr), and after 18 days' residence on Pikes Peak (4,300 m) while breathing ambient air (PIO2, 86 Torr) and air similar to that at sea level (35% O2, PIO2, 144 Torr). In both hypoxia and normoxia, after acclimatization the femoral arterial-iliac venous O2 content difference, hemoglobin concentration, and arterial O2 content, were higher than before acclimatization, but the venous PO2 (PVO2) was unchanged. Thermodilution leg blood flow was lower but calculated arterial O2 delivery and leg VO2 similar in hypoxia after vs. before acclimatization. Mean arterial pressure (MAP) and total peripheral resistance in hypoxia were greater after, than before, acclimatization. We concluded that acclimatization did not increase O2 delivery but rather maintained delivery via increased arterial oxygenation and decreased leg blood flow. The maintenance of PVO2 and the higher MAP after acclimatization suggested matching of O2 delivery to tissue O2 demands, with vasoconstriction possibly contributing to the decreased flow.

Melting Ice Rivers

2012 ◽  
Author(s):  
Cheryl Colopy
Keyword(s):  
Global Warming ◽  
Tibetan Plateau ◽  
The Netherlands ◽  
Sea Level ◽  
The Tibetan Plateau ◽  
Mount Everest ◽  
The Past ◽  
The North ◽  
The World ◽  
The Government

From a remote outpost of global warming, a summons crackles over a two-way radio several times a week: . . . Kathmandu, Tsho Rolpa! Babar Mahal, Tsho Rolpa! Kathmandu, Tsho Rolpa! Babar Mahal, Tsho Rolpa! . . . In a little brick building on the lip of a frigid gray lake fifteen thousand feet above sea level, Ram Bahadur Khadka tries to rouse someone at Nepal’s Department of Hydrology and Meteorology in the Babar Mahal district of Kathmandu far below. When he finally succeeds and a voice crackles back to him, he reads off a series of measurements: lake levels, amounts of precipitation. A father and a farmer, Ram Bahadur is up here at this frigid outpost because the world is getting warmer. He and two colleagues rotate duty; usually two of them live here at any given time, in unkempt bachelor quarters near the roof of the world. Mount Everest is three valleys to the east, only about twenty miles as the crow flies. The Tibetan plateau is just over the mountains to the north. The men stay for four months at a stretch before walking down several days to reach a road and board a bus to go home and visit their families. For the past six years each has received five thousand rupees per month from the government—about $70—for his labors. The cold, murky lake some fifty yards away from the post used to be solid ice. Called Tsho Rolpa, it’s at the bottom of the Trakarding Glacier on the border between Tibet and Nepal. The Trakarding has been receding since at least 1960, leaving the lake at its foot. It’s retreating about 200 feet each year. Tsho Rolpa was once just a pond atop the glacier. Now it’s half a kilometer wide and three and a half kilometers long; upward of a hundred million cubic meters of icy water are trapped behind a heap of rock the glacier deposited as it flowed down and then retreated. The Netherlands helped Nepal carve out a trench through that heap of rock to allow some of the lake’s water to drain into the Rolwaling River.

scholarly journals Oxygen affinity of blood in altitude Sherpas

1979 ◽  
Vol 47 (2) ◽  
pp. 337-341 ◽  
Author(s):  
M. Samaja ◽  
A. Veicsteinas ◽  
P. Cerretelli
Keyword(s):  
Sea Level ◽  
Concentration Ratio ◽  
Oxygen Affinity ◽  
Hemoglobin Concentration ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
Total Hemoglobin ◽  
The Mean ◽  
Total Hemoglobin Concentration ◽  
2,3 Dpg

Oxygen equilibrium curves on blood within 6 h from sampling have been estimated from polarographic measurements of oxyhemoglobin concentration, in 13 male 14- to 50-yr old Sherpas residing at 3,850 m above sea level (Kumjung, Nepal). In samples with red blood cell counts = 4.7 +/- 0.8 (SD) x 10(6)/mm3, total hemoglobin concentration [Hb] = 17.0 +/- 1.9 g/dl, and hematocrit = 53.3 +/- 5.0, the mean oxygen half-saturation of hemoglobin (P50) (pH = 7.4 and PCO2 = 40 Torr) was 27.3 +/- 1.8 Torr. The P50 of altitude Sherpas was not significantly different from that of acclimatized lowlanders (28.2 +/- 1.3; n = 7), sea-level Caucasian residents (26.5 +/- 1.0; n = 17), and Sherpas at sea level (27.1; n = 3). The 2,3-diphosphoglyceric acid-to-hemoglobin concentration ratio ([2,3-DPG]/[Hb]) in altitude Sherpas was 1.22 +/- 0.03, the same as that of acclimatized Caucasians (1.22 +/- 0.10). The Bohr effect measured for the blood of one altitude Sherpas by the ratio deltalog P50/deltapH was -0.32 and -0.45 at PCO2 levels of 40 and 20 Torr, respectively. These values are not significantly different from those found in Caucasians at sea level where deltalog P50/deltalpH was -0.35 and -0.42, respectively. It is concluded that the P50 in native highlanders is not significantly different from that observed in sea-level dwellers. [2,3-DPG]/[Hb] at altitude, both in natives and in newcomers, is 20% higher than in sea-level residents.

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