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

Journal of Applied Physiology

Volumn 116, Issue 7, 2014, Pages 893-904

  Petousi, Nayia ^a   Croft, Quentin P P ^a   Cavalleri, Gianpiero L ^b   Cheng, Hung Yuan ^a   Formenti, Federico ^c   Ishida, Koji ^d   Lunn, Daniel ^a   McCormack, Mark ^b   Shianna, Kevin V ^e   Talbot, Nick P ^a   Ratcliffe, Peter J ^c   Robbins, Peter A ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b ROYAL COLLEGE OF SURGEONS IN IRELAND   (Ireland)

^c UNIVERSITY OF OXFORD   (United Kingdom)

^d NAGOYA UNIVERSITY   (Japan)

^e DUKE UNIVERSITY   (United States)

Author keywords

EGLN1; EPAS1; Erythropoietin; High altitude; Hypoxic pulmonary vasoconstriction

Indexed keywords

BASIC HELIX LOOP HELIX TRANSCRIPTION FACTOR; EGLN1 PROTEIN, HUMAN; ENDOTHELIAL PAS DOMAIN-CONTAINING PROTEIN 1; EPO PROTEIN, HUMAN; ERYTHROPOIETIN; HEMOGLOBIN; HYPOXIA INDUCIBLE FACTOR PROLINE DIOXYGENASE; OXYGEN;

ACCLIMATIZATION; ADULT; ALTITUDE; ANOXIA; ASIAN CONTINENTAL ANCESTRY GROUP; BLOOD; CELL CULTURE; CHINA; COMPARATIVE STUDY; EPIDEMIOLOGY; ETHNOLOGY; GENE EXPRESSION REGULATION; GENETIC SELECTION; GENETIC TRANSCRIPTION; GENETICS; HAPLOTYPE; HUMAN; LUNG VENTILATION; MALE; METABOLISM; PATHOPHYSIOLOGY; PHENOTYPE; PULMONARY ARTERY; TIME; VASOCONSTRICTION; YOUNG ADULT;

ACCLIMATIZATION; ADULT; ALTITUDE; ANOXIA; ASIAN CONTINENTAL ANCESTRY GROUP; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; CELLS, CULTURED; CHINA; ERYTHROPOIETIN; GENE EXPRESSION REGULATION; HAPLOTYPES; HEMOGLOBINS; HUMANS; HYPOXIA-INDUCIBLE FACTOR-PROLINE DIOXYGENASES; MALE; OXYGEN; PHENOTYPE; PULMONARY ARTERY; PULMONARY VENTILATION; SELECTION, GENETIC; TIBET; TIME FACTORS; TRANSCRIPTION, GENETIC; VASOCONSTRICTION; YOUNG ADULT;

EID: 84901217970     PISSN: 87507587     EISSN: 15221601     Source Type: Journal    
DOI: 10.1152/japplphysiol.00535.2013     Document Type: Article

References (46)

1. Allemann Y, Sartori C, Lepori M, Pierre S, Melot C, Naeije R, Scherrer U, Maggiorini M. Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude. Am J Physiol Heart Circ Physiol 279: H2013-H2016, 2000.
2. Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, Liu E, Sergueeva AI, Miasnikova GY, Mole D, Maxwell PH, Stockton DW, Semenza GL, Prchal JT. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32: 614-621, 2002.
3. Balanos GM, Talbot NP, Robbins PA, Dorrington KL. Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans. Pflugers Arch 450: 372-380, 2005.
4. Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, Goldstein MC, Decker MJ, Vargas E, Villena M, Soria R, Alarcon AM, Gonzales C. Hemoglobin concentration of high-Altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 106: 385-400, 1998.
5. Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT. Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci USA 107: 11459-11464, 2010.
6. Beall CM, Strohl KP, Blangero J, Williams-Blangero S, Almasy LA, Decker MJ, Worthman CM, Goldstein MC, Vargas E, Villena M, Soria R, Alarcon AM, Gonzales C. Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives. Am J Phys Anthro-pol 104: 427-447, 1997.
7. Benyamin B, Ferreira MA, Willemsen G, Gordon S, Middelberg RP, McEvoy BP, Hottenga JJ, Henders AK, Campbell MJ, Wallace L, Frazer IH, Heath AC, de Geus EJ, Nyholt DR, Visscher PM, Penninx BW, Boomsma DI, Martin NG, Montgomery GW, Whitfield JB. Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet 41: 1173-1175, 2009.
8. Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, Lopez Herraez D, Brutsaert T, Parra EJ, Moore LG, Shriver MD. Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 6: e1001116, 2010.
9. Brooks JT, Elvidge GP, Glenny L, Gleadle JM, Liu C, Ragoussis J, Smith TG, Talbot NP, Winchester L, Maxwell PH, Robbins PA. Variations within oxygen-regulated gene expression in humans. J Appl Physiol 106: 212-220, 2009.
10. Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, Carmeliet P. Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest 111: 1519-1527, 2003.
11. Chambers JC, Zhang W, Li Y, Sehmi J, Wass MN, Zabaneh D, Hoggart C, Bayele H, McCarthy MI, Peltonen L, Freimer NB, Srai SK, Maxwell PH, Sternberg MJ, Ruokonen A, Abecasis G, Jarvelin MR, Scott J, Elliott P, Kooner JS. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet 41: 1170-1172, 2009.
12. Chemla D, Castelain V, Humbert M, Hebert JL, Simonneau G, Lecarpentier Y, Herve P. New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure. Chest 126: 1313-1317, 2004.
13. Clement ID, Robbins PA. Dynamics of the ventilatory response to hypoxia in humans. Respir Physiol 92: 253-275, 1993.
14. Dorrington KL, Clar C, Young JD, Jonas M, Tansley JG, Robbins PA. Time course of the human pulmonary vascular response to 8 hours of isocapnic hypoxia. Am J Physiol Heart Circ Physiol 273: H1126-H1134, 1997.
15. Formenti F, Beer PA, Croft QP, Dorrington KL, Gale DP, Lappin TR, Lucas GS, Maher ER, Maxwell PH, McMullin MF, O'Connor DF, Percy MJ, Pugh CW, Ratcliffe PJ, Smith TG, Talbot NP, Robbins PA. Cardiopulmonary function in two human disorders of the hypoxia-induc-ible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2{alpha} gain-of-function mutation. FASEB J 25: 2001-2011, 2011.
16. Gamboa A, Leon-Velarde F, Rivera-Ch M, Palacios JA, Pragnell TR, O'Connor DF, Robbins PA. Selected contribution: acute and sustained ventilatory responses to hypoxia in high-Altitude natives living at sea level. J Appl Physiol 94: 1255-1262; discussion 1253-1254, 2003.
17. Garruto RM, Chin CT, Weitz CA, Liu JC, Liu RL, He X. Hemato-logical differences during growth among Tibetans and Han Chinese born and raised at high altitude in Qinghai, China. Am J Phys Anthropol 122: 171-183, 2003.
18. Groves BM, Droma T, Sutton JR, McCullough RG, McCullough RE, Zhuang J, Rapmund G, Sun S, Janes C, Moore LG. Minimal hypoxic pulmonary hypertension in normal Tibetans at 3, 658 m. J Appl Physiol 74: 312-318, 1993.
19. Groves BM, Reeves JT, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM, Houston CS. Operation Everest II: elevated high-Altitude pulmonary resistance unresponsive to oxygen. J Appl Physiol 63: 521-530, 1987.
20. Howard LS, Barson RA, Howse BP, McGill TR, McIntyre ME, O'Connor DF, Robbins PA. Chamber for controlling end-tidal gas tensions over sustained periods in humans. J Appl Physiol 78: 1088-1091, 1995.
21. Jensen D, Wolfe LA, O'Donnell DE, Davies GA. Chemoreflex control of breathing during wakefulness in healthy men and women. J Appl Physiol 98: 822-828, 2005.
22. 2 of high-Altitude natives living at sea level. J Appl Physiol 81: 1605-1609, 1996.
23. O2 in humans. J Appl Physiol 81: 2274-2286, 1996.
24. Lorenzo FR, Simonson TS, Yang Y, Ge R, Prchal JT. A novel PHD2 mutation associated with Tibetan genetic adaptation to high altitude hypoxia. In: 52nd ASH Annual Meeting and Exposition, Orlando, FL. American Society of Hematology, 2010.
25. Moore LG. Comparative human ventilatory adaptation to high altitude. Respir Physiol 121: 257-276, 2000.
26. Moore LG, Armaza F, Villena M, Vargas E. Comparative aspects of high-Altitude adaptation in human populations. Adv Exp Med Biol 475: 45-62, 2000.
27. Moore LG, Curran-Everett L, Droma TS, Groves BM, McCullough RE, McCullough RG, Sun SF, Sutton JR, Zamudio S, Zhuang JG. Are Tibetans better adapted? Int J Sports Med 13, Suppl 1: S86-S88, 1992.
28. Peacock AJ, Challenor V, Sutherland G. Estimation of pulmonary artery pressure by Doppler echocardiography in normal subjects made hypoxic. Respir Med 84: 335-337, 1990.
29. Peng Y, Yang Z, Zhang H, Cui C, Qi X, Luo X, Tao X, Wu T, Ouzhuluobu, Basang, Ciwangsangbu, Danzengduojie, Chen H, Shi H, Su B. Genetic variations in Tibetan populations and high-Altitude adaptation at the Himalayas. Mol Biol Evol 28: 1075-1081, 2011.
30. Percy MJ, Beer PA, Campbell G, Dekker AW, Green AR, Oscier D, Rainey MG, van Wijk R, Wood M, Lappin TR, McMullin MF, Lee FS. Novel exon 12 mutations in the HIF2A gene associated with eryth-rocytosis. Blood 111: 5400-5402, 2008.
31. Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 358: 162-168, 2008.
32. Rivera-Ch M, Gamboa A, Leon-Velarde F, Palacios JA, O'Connor DF, Robbins PA. Selected contribution: high-Altitude natives living at sea level acclimatize to high altitude like sea-level natives. J Appl Physiol 94: 1263-1268; discussion 1253-1264, 2003.
33. Robbins PA, Swanson GD, Howson MG. A prediction-correction scheme for forcing alveolar gases along certain time courses. J Appl Physiol 52: 1353-1357, 1982.
34. Semenza GL. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood 114: 2015-2019, 2009.
35. Sime F, Penaloza D, Ruiz L. Bradycardia, increased cardiac output, and reversal of pulmonary hypertension in altitude natives living at sea level. Br Heart J 33: 647-657, 1971.
36. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R. Genetic evidence for high-Altitude adaptation in Tibet. Science 329: 72-75, 2010.
37. Skjaerpe T, Hatle L. Noninvasive estimation of systolic pressure in the right ventricle in patients with tricuspid regurgitation. Eur Heart J 7: 704-710, 1986.
38. Simonson TS and Powell FL. Less is more: blunted responses to hypoxia revealed in sea-level Tibetans. J Appl Physiol; doi:10.1152/ japplphysiol.01110.2013.
39. Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, Maxwell PH, McMullin MF, McNamara CJ, Percy MJ, Pugh CW, Ratcliffe PJ, Talbot NP, Treacy M, Robbins PA. Mutation of von Hippel-Lindau tumour suppressor and human cardiopul-monary physiology. PLoS Med 3: e290, 2006.
40. Soranzo N, Spector TD, Mangino M, Kuhnel B, Rendon A, Teumer A, Willenborg C, Wright B, Chen L, Li M, Salo P, Voight BF, Burns P, Laskowski RA, Xue Y, Menzel S, Altshuler D, Bradley JR, Bumpstead S, Burnett MS, Devaney J, Doring A, Elosua R, Epstein SE, Erber W, Falchi M, Garner SF, Ghori MJ, Goodall AH, Gwilliam R, Hakonar-son HH, Hall AS, Hammond N, Hengstenberg C, Illig T, Konig IR, Knouff CW, McPherson R, Melander O, Mooser V, Nauck M, Nieminen MS, O'Donnell CJ, Peltonen L, Potter SC, Prokisch H, Rader DJ, Rice CM, Roberts R, Salomaa V, Sambrook J, Schreiber S, Schunkert H, Schwartz SM, Serbanovic-Canic J, Sinisalo J, Siscovick DS, Stark K, Surakka I, Stephens J, Thompson JR, Volker U, Volzke H, Watkins NA, Wells GA, Wichmann HE, Van Heel DA, Tyler-Smith C, Thein SL, Kathiresan S, Perola M, Reilly MP, Stewart AF, Erdmann J, Samani NJ, Meisinger C, Greinacher A, Deloukas P, Ouwehand WH, Gieger C. A genome-wide meta-Analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 41: 1182-1190, 2009.
41. Vargas M, Leon-Velarde F, Monge CC, Palacios JA, Robbins PA. Similar hypoxic ventilatory responses in sea-level natives and high-Altitude Andean natives living at sea level. J Appl Physiol 84: 1024-1029, 1998.
42. White DP, Douglas NJ, Pickett CK, Weil JV, Zwillich CW. Sexual influence on the control of breathing. J Appl Physiol 54: 874-879, 1983.
43. Winslow RM, Chapman KW, Gibson CC, Samaja M, Monge CC, Goldwasser E, Sherpa M, Blume FD, Santolaya R. Different hemato-logic responses to hypoxia in Sherpas and Quechua Indians. J Appl Physiol 66: 1561-1569, 1989.
44. Xu S, Li S, Yang Y, Tan J, Lou H, Jin W, Yang L, Pan X, Wang J, Shen Y, Wu B, Wang H, Jin L. A genome-wide search for signals of high-Altitude adaptation in Tibetans. Mol Biol Evol 28: 1003-1011, 2011.
45. Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS, Zheng H, Liu T, He W, Li K, Luo R, Nie X, Wu H, Zhao M, Cao H, Zou J, Shan Y, Li S, Yang Q, Asan Ni P, Tian G, Xu J, Liu X, Jiang T, Wu R, Zhou G, Tang M, Qin J, Wang T, Feng S, Li G, Huasang Luosang J, Wang W, Chen F, Wang Y, Zheng X, Li Z, Bianba Z, Yang G, Wang X, Tang S, Gao G, Chen Y, Luo Z, Gusang L, Cao Z, Zhang Q, Ouyang W, Ren X, Liang H, Huang Y, Li J, Bolund L, Kristiansen K, Li Y, Zhang Y, Zhang X, Li R, Yang H, Nielsen R, Wang J. Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329: 75-78, 2010.
46. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation 70: 657-662, 1984.