Advertisement

High-Altitude Medicine: The Path from Genomic Insight to Clinical Applications

  • Soma Sarkar
Chapter

Abstract

Translation of research findings into clinical practice is an important aspect of medical progress. In context of high-altitude medical research, understanding the functions of all genes and their regulation under high-altitude environment is far from complete, and translation of genomics research findings into clinical practice is yet an unexplored domain. With advancement and accessibility to genomic and genomewide data sets, understanding of the role of genes and environment under high altitude will get accelerated which can potentially get converted to translational research.

Keywords

High Altitude Human Genome Project Acute Mountain Sickness Single Nucleotide Polymorphism Array Phosphoglycerate Mutase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Aggarwal S, Negi S, Jha P, Singh PK, Stobdan T, Pasha MAQ, Ghosh S, Agrawal A, Praasher B, Mukerji M (2010) EGLN1 involvement in high-altitude adaptation revealed through genetic analysis of extreme constitution types defined in Ayurveda. Proc Natl Acad Sci U S A 107:18961–18966PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Ahsan A, Charu R, Pasha MA, Norboo T, Charu R, Afrin F, Ahsan A, Baig MA (2004) eNOS allelic variants at the same locus associate with HAPE and adaptation. Thorax 59:1000–1002PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Aldashev AA (2007) Gene polymorphisms and high altitude pulmonary hypertension. In: Aldashev AA, Naeije R (eds) Problems of high altitude medicine and biology. Springer, New York, pp 151–168CrossRefGoogle Scholar
  4. 4.
    Aldashev AA, Sarybaev AS, Sydykov AS et al (2002) Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Respir Crit Care Med 166:1396–1402PubMedCrossRefGoogle Scholar
  5. 5.
    Baillie JK, Thompson AA, Irving JB, Bates MG, Sutherland AI, Macnee W, Maxwell SR, Webb DJ (2009) Oral antioxidant supplementation does not prevent acute mountain sickness: double blind randomized placebo-controlled trial. QJM 102:341–348PubMedCrossRefGoogle Scholar
  6. 6.
    Bartsch P, Maggiorini M, Schobersberger W, Shaw S, Rascher W, Girard J, Weidmann P, Oelz O (1991) Enhanced exercise induced rise of aldosterone and vasopressin preceding mountain sickness. J Appl Physiol 71:136–143PubMedGoogle Scholar
  7. 7.
    Bates MG, Thompson AA, Baillie JK (2007) Phosphodiesterase type 5 inhibitors in the treatment and prevention of high altitude pulmonary edema. Curr Open Invest Drugs 8:226–231Google Scholar
  8. 8.
    Basnyat B, Murdoch DR (2003) High-altitude illness. Lancet 361:1967–1974PubMedCrossRefGoogle Scholar
  9. 9.
    Basnyat B, Gertsch JH, Holck PS et al (2006) Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the Prophylactic Acetazolamide Dosage Comparison for Efficacy (PACE) trial. High Alt Med Biol 7:17–27PubMedCrossRefGoogle Scholar
  10. 10.
    Beall CM (2000) Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol 72:201–228PubMedGoogle Scholar
  11. 11.
    Beall CM, Decker MJ, Brittenham GM, Kushner I, Gebremedhin A, Strohl KP (2002) An Ethiopian pattern of human adaptation to high-altitude hypoxia. Proc Natl Acad Sci U S A 99:17215–17218PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C et al (2010) Natural selection on EPAS1 (HIF2alpha) associated with low haemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A 107:11459–11464PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Berglund B (1992) High-altitude training aspects of haematological adaptation. Sports Med 14:289–303PubMedCrossRefGoogle Scholar
  14. 14.
    Bigham A, Mao X, Mei R, Brutsaert T, Wilson MJ, Julian CG, Parra EJ, Akey JM, Moore LG, Shriver MD (2009) Identifying positive selection candidate loci for high-altitude adaptation in Andean populations. Hum Genomics 4:79–90PubMedPubMedCentralGoogle Scholar
  15. 15.
    Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, López Herráez D, Brutsaert T, Parra EJ, Moore LG, Shriver MD (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 6:e100111CrossRefGoogle Scholar
  16. 16.
    Biolo A, Greferath R, Siwik DA, Qin F, Valsky E, Fylaktakidou KC, Pothukanuri S, Duarte CD, Schwarz RP, Lehn JM, Nicolau C, Colucci WS (2009) Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo-inositol trispyrophosphate. Proc Natl Acad Sci U S A 106:1926–1929PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Bryant JA, Atherton MA, Collins MW (2007) Design and Information in Biology. From Molecules to System. WIT Press, Southampton, p 108Google Scholar
  18. 18.
    Cain SM, Dunn JE (1966) Low doses of acetazolamide to aid accommodation of men to altitude. J Appl Physiol 21:1195–1200PubMedGoogle Scholar
  19. 19.
    Charu R, Stobdan T, Ram RB, Khan AP, Pash MAQ, Norboo T, Afrin F (2006) Susceptibility to high altitude pulmonary oedema: role of ACE and ET-1 polymorphisms. Thorax 61:1011–1012PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Clerici C, Planes C (2009) Gene regulation in the adaptive process to hypoxia in long epithelial call. Am J Physiol Lung Cell Mol Physiol 296:L267–L274PubMedCrossRefGoogle Scholar
  21. 21.
    Droma Y, Hanaoka M, Hotta J, Katsuyama Y, Ota M, Kobayashi T, Kubo K (2003) The r506 Q mutation of coagulation factor V gene in high altitude pulmonary edema susceptible subjects. High Alt Med Biol 4:497–498PubMedCrossRefGoogle Scholar
  22. 22.
    Denhert C, Grunig E, Mereles D, von Lennep N, Bartsch P (2005) Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude. Eur Respir J 25:545–551CrossRefGoogle Scholar
  23. 23.
    Ferrazzini G, Maggiorini M, Kriemler S, Bartsch P, Oelz O (1987) Successful treatment of acute mountain sickness with dexamethasone. Br Med J (Clin Res Ed) 294:1380–1382CrossRefGoogle Scholar
  24. 24.
    Flowers J, Sezgin E, Kumagai S, Duvernell D, Matzkin L, Schmidt P et al (2007) Adaptive evolution of metabolic pathways in Drosophila. Mol Biol Evol 24:1347–1354PubMedCrossRefGoogle Scholar
  25. 25.
    Forwand SA, Landowne M, Follansbee JN, Hansen JE (1968) Effect of acetazolamide on acute mountain sickness. N Engl J Med 279(16):839–845PubMedCrossRefGoogle Scholar
  26. 26.
    Fulco CS, Ditzler D, Soares R, Lammi E, Muza SR, DW Degroot (2002) Effect of acetazolamide on isolated quadriceps muscle endurance performance at sea level and during acute altitude exposure. US Army Research Institute of Environmental Medicine Technical Report no T 02/9Google Scholar
  27. 27.
    Grant KP, Nicholas PH, Constance B, Gertssch J (2012) Ibuprofen prevents altitude illness a randomized controlled trial for prevention of altitude illness with non-steroidal anti-inflammatory. Ann Emerg Med 59:484–490CrossRefGoogle Scholar
  28. 28.
    Gracey AY (2007) Interpreting physiological responses to environmental change through gene expression profiling. J Exp Biol 210:1584–1592PubMedCrossRefGoogle Scholar
  29. 29.
    Gracey AY, Cossins AR (2003) Application of microarray technology in environmental and comparative physiology. Ann Rev Physiol 65:231–259CrossRefGoogle Scholar
  30. 30.
    Gertsch JH, Lipman GS, Kanaan NC, Holck PS (2012) Altitude sickness in climbers and efficacy of NSAIDs trial (ASCENT) randomized controlled trial of Ibuprofen versus placebo for prevention of altitude illness. Wilderness and Environ Med 23:307–315CrossRefGoogle Scholar
  31. 31.
    Gelfi C, De Palma S, Ripamonti M, Eberin I, Cerretelli P (2004) New aspects of altitude adaptation in Tibetans: a proteomic approach. FASEB J 18:612–614PubMedGoogle Scholar
  32. 32.
    Grocott MPW, Martin DS, Levett DZH, McMorrow R, Windsor J, Montgomery HE (2009) Arterial blood gases and oxygen content in climbers on Mount Everest. N Engl J Med 360:140–149PubMedCrossRefGoogle Scholar
  33. 33.
    Grissom CK, Roach RC, Sarnquist FH, Hackett PH (1992) Acetazolamide in the treatment of acute mountain sickness clinical efficacy and effect on gas exchange. Ann Intern Med 116:461–465PubMedCrossRefGoogle Scholar
  34. 34.
    Hochachka PW, Rupert JL (2003) Fine tuning the HIF-1 global O2 sensor for hypobaric hypoxia in Andean high-altitude natives. Biol Essays 25:515–519Google Scholar
  35. 35.
    Hackett PH, Roach RC (2001) High altitude illness. N Engl J Med 345:107–114PubMedCrossRefGoogle Scholar
  36. 36.
    Hackett PH, Roach RC, Wood RA et al (1988) Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space Environ Med 59:950–954PubMedGoogle Scholar
  37. 37.
    Hackett P, Shlim D (2009) The pre-travel consultation – self-treatable diseases – altitude illness. In: Turell D, Brunette G, Kozarsky P, St. Louis Mosby, Lefor A (eds) CDC health information for international travel 2010 “The Yellow Book”. St. Louis. Mosby. ISBN 0-7020-3481-9Google Scholar
  38. 38.
    Hsu AR, Barnholt KE, Grundmann NK, Lin JH, McCallum SW, Friedlander AL (2006) Sildenafil improves cardiac output and exercise performance during acute hypoxia, but not normoxia. J Appl Physiol 100:2031–2040PubMedCrossRefGoogle Scholar
  39. 39.
    Hultgren HN, Spickard WB, Hellriegel K, Houston CS (1961) High altitude pulmonary edema. Medicine (Baltimore) 40:289–313CrossRefGoogle Scholar
  40. 40.
    Jafarian S, Gorouhi F, Salimi S, Lotfi J (2007) Sumatriptan for prevention of acute mountain sickness: randomized clinical trial. Ann Neurol 62:273–277PubMedCrossRefGoogle Scholar
  41. 41.
    Janssens AC, van Duijin CM (2008) Genome-based prediction of common diseases: advances and prospects. Hum Mol Genet 17:166–173CrossRefGoogle Scholar
  42. 42.
    León-Velarde F, Mejía O (2008) Gene expression in chronic high altitude diseases. High Alt Med Biol 9:130–139PubMedCrossRefGoogle Scholar
  43. 43.
    Levine BD, Yoshimura K, Kobayashi T, Fukushima M, Shibamoto T, Ueda G (1989) Dexamethasone in the treatment of acute mountain sickness. N Engl J Med 321:1707–1713PubMedCrossRefGoogle Scholar
  44. 44.
    Li FZ, Zhou F, Jiang CZ, Sun SY, He MA, Zhang SY, Liao R, Zeng HS, Wu YM, Wu TC (2004) Relationship between heat stress protein 70 gene polymorphisms and the risk of acute mountain sickness. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 22:413–415 (article in Chinese)PubMedGoogle Scholar
  45. 45.
    Lipman JS, Kanan NC, Holck PS, Constance BB, Gertsc JH (2012) Ibuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories. Ann Emerg Med 58:484–490CrossRefGoogle Scholar
  46. 46.
    Lockhart DJ, Winzeler EA (2000) Genomics, gene expression and DNA arrays. Nature 405:827–836PubMedCrossRefGoogle Scholar
  47. 47.
    Lorenzo VF, Yang Y, Simonson TS, Nussenzvei R, Jorde LB, Prchal JT, Ge RL (2009) Genetic adaptation to extreme hypoxia: study of high-altitude pulmonary edema in a three generation Han Chinese family. Blood Cells Mol Dis 42:221–225CrossRefGoogle Scholar
  48. 48.
    Maclnnis MJ, Michael SK, Jim LR (2010) Evidence for a genetic basis for altitude illness: 2010 update. High Alt Med Biol 11:349–368CrossRefGoogle Scholar
  49. 49.
    Maggiorini M, Brunner La Rocca HP, Peth S et al (2006) Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial. Ann Intern Med 145:497–506PubMedCrossRefGoogle Scholar
  50. 50.
    Manolio TA, Collins FS, Cox NJ et al (2009) Finding the missing heritability of complex diseases. Nature 461:747–753PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Mejia OM, Prchal JT, Leon-Velarde F, Hurtado A, Stockton DW (2005) Genetic association analysis of chronic mountain sickness in an Andean high-altitude population. Haematologica 90:13–19PubMedGoogle Scholar
  52. 52.
    Mishra A, Mohammad G, Thinlas T, Pasha MAQ (2013) EGLN1 variants influence expression and SaO2 levels to associate with high-altitude pulmonary oedema and adaptation. Clin Sci 124:479–489PubMedGoogle Scholar
  53. 53.
    Montgomery HE, Marshall R, Hemingway H et al (1998) Human gene for physical performance. Nature 393:221–222PubMedCrossRefGoogle Scholar
  54. 54.
    Muza SR, Fulco CS, Cymerman A (2004) Altitude acclimatization guide. USARIEM Technical Note TN 04-05Google Scholar
  55. 55.
    Norboo T, Saiyed HN, Angchuk PT, Tsering P, Angchuk ST, Phuntsog ST, Yahya M, Wood S, Bruce NG, Ball KP (2004) Mini review of high altitude health problems in Ladakh. Biomed. Pharmacotherapy 58:220–225CrossRefGoogle Scholar
  56. 56.
    Oelz O, Maggiorini M, Ritter M et al (1989) Nifedipine for high altitude pulmonary oedema. Lancet 2:1241–1244PubMedCrossRefGoogle Scholar
  57. 57.
    Orringer CE (2013) Non-HDL Cholesterol, ApoB and LDL particle concentration in coronary heart disease risk prediction and treatment. Clin Lipidol 8:69–79CrossRefGoogle Scholar
  58. 58.
    Pandey A, Mann M (2000) Proteomics to study genes and genomes. Nature 405:837–846PubMedCrossRefGoogle Scholar
  59. 59.
    Penaloza D, Arias-Stella J (2007) Healthy highlanders and chronic mountain sickness. Circulation 115:1132–1146PubMedCrossRefGoogle Scholar
  60. 60.
    Pasha MAQ, Khan AP, Kumar R et al (2001) Angiotensin converting enzyme insertion allele in relation to high altitude adaptation. Ann Hum Genet 65:531–536CrossRefGoogle Scholar
  61. 61.
    Pasha MAQ, Charu R, Ahsan A, Norboo T (2005) HAPE susceptibility associates with variants of genes of vascular homeostasis. Human Genome Meeting (HUGO HGM). Poster abstract 310Google Scholar
  62. 62.
    Qi Y, Niu W, Zhu T, Zhou W, Qiu C (2008) Synergistic effect of the genetic polymorphisms of the rennin- angiotensin aldosterone system on high altitude pulmonary edema: a study from Qinghai-Tibet altitude. Eur J Epidemiol 23:143–152PubMedCrossRefGoogle Scholar
  63. 63.
    Qi Y, Niu WQ, Zhu TC, Liu JL, Dong WY, Xu Y, Ding SQ, Cui CB, Pan YJ, Yu GS et al (2009) Genetic interaction of Hsp70 family genes polymorphisms with high-altitude pulmonary edema among Chinese railway constructors at altitudes exceeding 4000 meters. Clin Chim Acta 405:17–22PubMedCrossRefGoogle Scholar
  64. 64.
    Qi L, Yang L, Chen H (2011) Detecting and quantitating physiological ER stress in mammals. Methods Enzymol 490:137–146PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Rajput C, Arif E, Vibhuti A, Stobdan T, Khan AP, Norboo T, Afrin F, Qadar Pasha MA (2006) Predominance of interaction among wild-type alleles of CYP11B2 in Himalayan native associates with high-altitude adaptation. Biochem Biophys Res Commun 348:735–740PubMedCrossRefGoogle Scholar
  66. 66.
    Richalet JP, Larmiqnat P, Poitrine E, Letournel M, Canoui-Poitrine F (2012) Physiological risk factors for severe high altitude illness: a prospective cohort study. Am J Respir Crit Care Med 185:192–198PubMedCrossRefGoogle Scholar
  67. 67.
    Rupert JL, Kidd KK, Norman LE, Monsalve MV, Hochachka PW, Devine DV (2003) Genetic polymorphisms in the rennin-angiotensin system in high-altitude and low-altitude native American populations. Ann Hum Genet 67:17–25PubMedCrossRefGoogle Scholar
  68. 68.
    Stobdan TA, Khan Z, Nejatizadeh AP, Ram A, Thinlas R, Mohammad T, Norboo G, Himashree T, Pasha G, MAQ (2011) Polymorphisms of renin-angiotensin system genes as a risk factor for high-altitude pulmonary oedema. J Renin Angiotensin Aldosterone Syst 12:93–101PubMedCrossRefGoogle Scholar
  69. 69.
    Sarkar S, Banerjee PK, Selvamurthy W (2003) High altitude hypoxia: an intricate inerplay of oxygen responsive macroevents and micromolecules. Mol Cell Biochem 253:287–305PubMedCrossRefGoogle Scholar
  70. 70.
    Sarkar S (2012) Hypoxic signature of high altitude acclimatization: a gene expression study. Ind J Aerosp Med 56:1–10Google Scholar
  71. 71.
    Saxena S, Kumar R, Madan T, Gupta V, Muralidhar K, Sarma PU (2005) Association of polymorphisms in pulmonary surfactant protein A1 and A2 gene with high-altitude pulmonary edema. Chest 128:1611–1619PubMedCrossRefGoogle Scholar
  72. 72.
    Scheinfeldt LB, Soi S, Thompson S, Ranciaro A, Woldemeskel D, Beggs W, Charla Lambert C, Jarvis JP, Abate D, Belay G, Tishkoff SA (2012) Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol 13:R1PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Sharma M, Singh SB, Sarkar S (2014) Genomewide expression analysis suggests perturbation of vascular homeostatis during high attitude pulmonary edema. Plos One 9:e85902Google Scholar
  74. 74.
    Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R (2010) Genetic evidence for high-altitude adaptation in Tibet. Science 329:72–75PubMedCrossRefGoogle Scholar
  75. 75.
    Srivastava S, Bhagi S, Kumari B, Chandra K, Sarkar S, Ashraf MZ (2011) Association of polymorphisms in angiotensin and aldosterone synthase genes of the renin–angiotensin–aldosterone system with high-altitude pulmonary edema. JRAAS 13:155–160PubMedGoogle Scholar
  76. 76.
    Storz JF, Lockhart DJ, Winzeler E, Scott GR, Cheviron ZA (2010) Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates. Nature 405:827Google Scholar
  77. 77.
    Teppema LJ, Balanos GM, Steinback CD et al (2007) Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia. Am J Respir Crit Care Med 175:277–281PubMedCrossRefGoogle Scholar
  78. 78.
    van Patot MC, Leadbetter G, Keyes LE, Maakestad KM, Olson S, Hackett PH (2008) Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness. High Alt Med Biol 9:289–293PubMedCrossRefGoogle Scholar
  79. 79.
    Wang P, Koehle MS, Rupert JL (2009) Genotype at the missense G894T polymorphism (Glu298Asp) in the NOS3 gene is associated with the susceptibility to acute mountain sickness. High Alt Med Biol 10:261–267PubMedCrossRefGoogle Scholar
  80. 80.
    Wang P, Ha AY, Kidd KK, Koehle MS, Rupert JL (2010) A variant of the endothelial nitric oxide synthase gene (NOS3) associated with AMS susceptibility is less common in the Quechua a high altitude Native population. High Alt Med Biol 11:27–30PubMedCrossRefGoogle Scholar
  81. 81.
    Wagner A (2009) Evolutionary constraints permeate large metabolic networks. BMC Evol Biol 9:231PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Wagner DR, Fargo JD, Parker D, Tatsugawa K, Young TA (2006) Variables contributing to acute mountain sickness on the summit of Mt. Whitney. Wilderness Environ Med 17:221–228PubMedCrossRefGoogle Scholar
  83. 83.
    Watson JD, Crick FHC (1933) A structure of deoxyribose nucleic acid. Nature 171:737–738CrossRefGoogle Scholar
  84. 84.
    Wu T, Li S, Ward MP (2005) Tibetans at extreme altitude. Wilderness Environ Med 16:47–54PubMedCrossRefGoogle Scholar
  85. 85.
    Wu TY, Ding SQ, Liu JL, Yu MT, Jia JH, Duan JQ, Chai ZC, Dai RC, Zhang SL, Liang BZ et al (2009) Reduced incidence and severity of acute mountain sickness in Qinghai- Tibet railroad construction workers after repeated 7 month exposures despite 5 month low altitude periods. High Alt Med Biol 10:221–232PubMedCrossRefGoogle Scholar
  86. 86.
    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 (2011) A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol Biol Evol 28:1003–1011PubMedCrossRefGoogle Scholar
  87. 87.
    Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZXP, Pool JE, Xu X, Jiang H et al (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329:75–78PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Zhou D, Udpa N, Ronen R, Stobdan T, Liang J, Appenzeller O, Zhao HW, Yin Y, Du Y, Guo L, Cao R, Wang Y, Jin X, Huang C, Jia W, Cao D, Guo G, Gamboa JL, Villafuerte F, Callacondo D, Xue J, Liu S, Frazer KA, Li Y, Bafna V, Haddad GG (2013) Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders. Am J Hum Genet 93:452–462PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  1. 1.Defence Institute of Physiology and Allied Sciences (DIPAS)New DelhiIndia

Personalised recommendations