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Functional & Integrative Genomics

, Volume 19, Issue 1, pp 205–215 | Cite as

Global expression profiling and pathway analysis in two different population groups in relation to high altitude

  • Supriya Saini
  • Praveen VatsEmail author
  • Susovon Bayen
  • Priya Gaur
  • Koushik Ray
  • Krishna Kishore
  • Meerim Sartmyrzaeva
  • Almaz Akunov
  • Abdirashit Maripov
  • Akpay Sarybaev
  • Bhuvnesh Kumar
  • Shashi Bala Singh
Original Article

Abstract

High altitude (HA) is associated with number of stresses. Response of these stresses may vary in different populations depending upon altitude, duration of residency, ancestry, geographical variation, lifestyle, and ethnicities. For understanding population variability in transcriptome, array-based global gene expression profiling was performed on extracted RNA of male volunteers of two different lowland population groups, i.e., Indians and Kyrgyz, at baseline and day 7 of HA exposure (3200 m). A total of 97 genes were differentially expressed at basal in Kyrgyz as compared to Indians (82 downregulated and 15 upregulated), and 196 were differentially expressed on day 7 of HA (118 downregulated and 78 upregulated). Ingenuity Pathway Analysis and gene ontology highlighted eIF2 signaling with most significant negative activation z score at basal in Kyrgyz compared to Indians with downregulation of various L- and S-ribosomal proteins indicating marked translational repression. On day 7, cAMP-mediated signaling is most enriched with positive activation z score in Kyrgyz compared to Indians. Plasma cAMP levels were higher in Kyrgyz on day 7 compared to Indians. Extracellular adenosine levels were elevated in both the groups upon HA, but higher in Kyrgyz compared to Indians. Valedictory qRT-PCR showed upregulation of ADORA2B and CD73 along with downregulation of ENTs in Kyrgyz compared to Indians indicating elevated levels of extracellular nucleotides mainly adenosine and activation of extracellular cAMP-adenosine pathway which as per literature triggers endogenous protective mechanisms under stress conditions like hypoxia. Thus, transcriptome changes at HA are population-specific, and it may be necessary to take care while interposing similar results in different populations.

Keywords

Hypoxia High altitude Adenosine Acclimatization 

Notes

Acknowledgements

The authors are grateful to the troops of the Indian and Kyrgyz Army for volunteering to participate in the study. We express our gratitude to DGAFMS and SD branch for their support. We also acknowledge Mr. Karan Pal and Mr. Alpesh Kumar Sharma of our lab for their valuable support in the study.

Author contribution

PV was involved in the study concept, design, data acquisition, and drafting of the manuscript. SS wrote the paper and was involved in data acquisition, interpretation, analysis, and drafting the work for important intellectual content. SB, PG, KR, KK, MS, AA, and AM were involved in data acquisition and coordination of study process. BK was involved in drafting and revising the work for important intellectual content. AS and SBS have set up the study concept and design and were responsible for drafting of the manuscript, supervision, and coordination of study process. All the authors approved the final version of the manuscript.

Funding

The work is funded by the Defence Institute of Physiology and Allied Sciences (DIPAS), Defence R&D Organization (DRDO).

Compliance with ethical standards

The study conformed to the Ethical guidelines of the institute and in accordance with Helsinki declaration.

Competing interests

The authors declare that they have no conflict of interest.

Supplementary material

10142_2018_637_MOESM1_ESM.xlsx (25 kb)
ESM 1 (XLSX 25 kb)

References

  1. Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV, Mamanova LB, Maripov R, Kojonazarov BK, Mirrakhimov MM, Wilkins MR, Morrell NW (2002) Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Respir Crit Care Med 166:1396–1402.  https://doi.org/10.1164/rccm.200204-345OC CrossRefPubMedGoogle Scholar
  2. Bando T, Albes JM, Schone J, Wada H, Hitomi S, Wahlers T, Schafers HJ (2000) Significance of cyclic adenosine monophosphate and nitroglycerin in ET-Kyoto solution for lung preservation. Ann Thorac Surg 69:887–891 discussion 891-882CrossRefGoogle Scholar
  3. Beall CM (2006) Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Integr Comp Biol 46:18–24.  https://doi.org/10.1093/icb/icj004 CrossRefPubMedGoogle Scholar
  4. Bull TM, Coldren CD, Geraci MW, Voelkel NF (2007) Gene expression profiling in pulmonary hypertension. Proc Am Thorac Soc 4:117–120.  https://doi.org/10.1513/pats.200605-128JG CrossRefPubMedGoogle Scholar
  5. Calvano SE et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437:1032–1037.  https://doi.org/10.1038/nature03985 CrossRefPubMedGoogle Scholar
  6. Chen F, Zhang W, Liang Y, Huang J, Li K, Green CD, Liu J, Zhang G, Zhou B, Yi X, Wang W, Liu H, Xu X, Shen F, Qu N, Wang Y, Gao G, San A, JiangBai LS, Sang H, Fang X, Kristiansen K, Yang H, Wang J, Han JDJ, Wang J (2012) Transcriptome and network changes in climbers at extreme altitudes. PLoS One 7:e31645.  https://doi.org/10.1371/journal.pone.0031645 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets--what are the challenges? Nat Rev Drug Discov 12:265–286.  https://doi.org/10.1038/nrd3955 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Colgan SP, Eltzschig HK, Eckle T, Thompson LF (2006) Physiological roles for ecto-5′-nucleotidase (CD73). Purinergic Signalling 2:351–360.  https://doi.org/10.1007/s11302-005-5302-5 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Davies J, Karmouty-Quintana H, le TT, Chen NY, Weng T, Luo F, Molina J, Moorthy B, Blackburn MR (2014) Adenosine promotes vascular barrier function in hyperoxic lung injury. Phys Rep 2:e12155.  https://doi.org/10.14814/phy2.12155 CrossRefGoogle Scholar
  10. Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF, Eltzschig HK (2008) A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 111:2024–2035.  https://doi.org/10.1182/blood-2007-10-117044 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Eltzschig HK, Faigle M, Knapp S, Karhausen J, Ibla J, Rosenberger P, Odegard KC, Laussen PC, Thompson LF, Colgan SP (2006) Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26. Blood 108:1602–1610.  https://doi.org/10.1182/blood-2006-02-001016 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Fan J, Zhang C, Chen Q, Zhou J, Franc JL, Chen Q, Tong Y (2016) Genomic analyses identify agents regulating somatotroph and lactotroph functions. Funct Integr Genomics 16:693–704.  https://doi.org/10.1007/s10142-016-0518-8 CrossRefPubMedGoogle Scholar
  13. Gladwin MT (2011) Adenosine receptor crossroads in sickle cell disease. Nat Med 17:38–40.  https://doi.org/10.1038/nm0111-38 CrossRefPubMedGoogle Scholar
  14. Goel A, Goyal M, Singh R, Verma N, Tiwari S (2015) Diurnal variation in peak expiratory flow and forced expiratory volume. J Clin Diagn Res 9:CC05–CC07.  https://doi.org/10.7860/JCDR/2015/15156.6661 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108CrossRefGoogle Scholar
  16. Iacobas DA, Fan C, Iacobas S, Haddad GG (2008) Integrated transcriptomic response to cardiac chronic hypoxia: translation regulators and response to stress in cell survival. Funct Integr Genomics 8:265–275.  https://doi.org/10.1007/s10142-008-0082-y CrossRefPubMedPubMedCentralGoogle Scholar
  17. Jackson EK, Dubey RK (2001) Role of the extracellular cAMP-adenosine pathway in renal physiology. Am J Physiol Renal Physiol 281:F597–F612CrossRefGoogle Scholar
  18. Jackson EK, Mi Z, Dubey RK (2007) The extracellular cAMP-adenosine pathway significantly contributes to the in vivo production of adenosine. J Pharmacol Exp Ther 320:117–123.  https://doi.org/10.1124/jpet.106.112748 CrossRefPubMedGoogle Scholar
  19. Jackson EK, Ren J, Mi Z (2009) Extracellular 2′,3′-cAMP is a source of adenosine. J Biol Chem 284:33097–33106.  https://doi.org/10.1074/jbc.M109.053876 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Jia C, Kong X, Koltes JE, Gou X, Yang S, Yan D, Lu S, Wei Z (2016) Gene co-expression network analysis unraveling transcriptional regulation of high-altitude adaptation of Tibetan pig. PLoS One 11:e0168161.  https://doi.org/10.1371/journal.pone.0168161 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Joshi B, Cameron A, Jagus R (2004) Characterization of mammalian eIF4E-family members. Eur J Biochem 271:2189–2203.  https://doi.org/10.1111/j.1432-1033.2004.04149.x CrossRefPubMedGoogle Scholar
  22. Kudo LC, Parfenova L, Vi N, Lau K, Pomakian J, Valdmanis P, Rouleau GA, Vinters HV, Wiedau-Pazos M, Karsten SL (2010) Integrative gene-tissue microarray-based approach for identification of human disease biomarkers: application to amyotrophic lateral sclerosis. Hum Mol Genet 19:3233–3253.  https://doi.org/10.1093/hmg/ddq232 CrossRefPubMedGoogle Scholar
  23. Li K, Gesang L, Dan Z, Gusang L (2016) Genome-wide transcriptional analysis reveals the protection against hypoxia-induced oxidative injury in the intestine of Tibetans via the inhibition of GRB2/EGFR/PTPN11 pathways. Oxidative Med Cell Longev 2016:6967396:1–13.  https://doi.org/10.1155/2016/6967396 CrossRefGoogle Scholar
  24. Li K, Gesang L, Dan Z, Gusang L (2017) Transcriptome reveals the overexpression of a kallikrein gene cluster (KLK1/3/7/8/12) in the Tibetans with high altitude-associated polycythemia. Int J Mol Med 39:287–296.  https://doi.org/10.3892/ijmm.2016.2830 CrossRefPubMedGoogle Scholar
  25. Liu B, Qian SB (2014) Translational reprogramming in cellular stress response. Wiley Interdiscip Rev RNA 5:301–315.  https://doi.org/10.1002/wrna.1212 CrossRefPubMedGoogle Scholar
  26. Liu H, Zhang Y, Wu H, D’Alessandro A, Yegutkin GG, Song A, Sun K, Li J, Cheng NY, Huang A, Edward Wen Y, Weng TT, Luo F, Nemkov T, Sun H, Kellems RE, Karmouty-Quintana H, Hansen KC, Zhao B, Subudhi AW, Jameson-van Houten S, Julian CG, Lovering AT, Eltzschig HK, Blackburn MR, Roach RC, Xia Y (2016) Beneficial role of erythrocyte adenosine A2B receptor-mediated AMP-activated protein kinase activation in high-altitude hypoxia. Circulation 134:405–421.  https://doi.org/10.1161/CIRCULATIONAHA.116.021311 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Liu X, Zheng Z, Chen C, Guo S, Liao Z, Li Y, Zhu Y, Zou H, Wu J, Xie W, Zhang P, Xu L, Wu B, Li E (2017) Network analyses elucidate the role of SMYD3 in esophageal squamous cell carcinoma. FEBS Open Bio 7:1111–1125.  https://doi.org/10.1002/2211-5463.12251 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Maere S, Heymans K, Kuiper M (2005) BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21:3448–3449.  https://doi.org/10.1093/bioinformatics/bti551 CrossRefPubMedGoogle Scholar
  29. Martin DS, Gilbert-Kawai E, Levett D, Mitchell K, Kumar Bc R, Mythen MG, Grocott MP (2013) Xtreme Everest 2: unlocking the secrets of the Sherpa phenotype? Extreme Physiol Med 2:30.  https://doi.org/10.1186/2046-7648-2-30 CrossRefGoogle Scholar
  30. Qiu Q, Zhang G, Ma T, Qian W, Wang J, Ye Z, Cao C, Hu Q, Kim J, Larkin DM, Auvil L, Capitanu B, Ma J, Lewin HA, Qian X, Lang Y, Zhou R, Wang L, Wang K, Xia J, Liao S, Pan S, Lu X, Hou H, Wang Y, Zang X, Yin Y, Ma H, Zhang J, Wang Z, Zhang Y, Zhang D, Yonezawa T, Hasegawa M, Zhong Y, Liu W, Zhang Y, Huang Z, Zhang S, Long R, Yang H, Wang J, Lenstra JA, Cooper DN, Wu Y, Wang J, Shi P, Wang J, Liu J (2012) The yak genome and adaptation to life at high altitude. Nat Genet 44:946–949.  https://doi.org/10.1038/ng.2343 CrossRefPubMedGoogle Scholar
  31. Semenza GL (2007) Life with oxygen. Science 318:62–64.  https://doi.org/10.1126/science.1147949 CrossRefPubMedGoogle Scholar
  32. Sethy NK, Singh M, Kumar R, Ilavazhagan G, Bhargava K (2011) Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia. Funct Integr Genomics 11:119–137.  https://doi.org/10.1007/s10142-010-0195-y CrossRefPubMedGoogle Scholar
  33. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504CrossRefGoogle Scholar
  34. Sharma M, Singh SB, Sarkar S (2014) Genome wide expression analysis suggests perturbation of vascular homeostasis during high altitude pulmonary edema. PLoS One 9:e85902.  https://doi.org/10.1371/journal.pone.0085902 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Soma S (2012) Hypoxic signature of high altitude acclimatization: a gene expression study. Ind J Aerospace Med 56:1Google Scholar
  36. Song A, Zhang Y, Han L, Yegutkin GG, Liu H, Sun K, D’Alessandro A, Li J, Karmouty-Quintana H, Iriyama T, Weng T, Zhao S, Wang W, Wu H, Nemkov T, Subudhi AW, Jameson-van Houten S, Julian CG, Lovering AT, Hansen KC, Zhang H, Bogdanov M, Dowhan W, Jin J, Kellems RE, Eltzschig HK, Blackburn M, Roach RC, Xia Y (2017) Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent. Nat Commun 8:14108.  https://doi.org/10.1038/ncomms14108 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Storz JF, Moriyama H (2008) Mechanisms of hemoglobin adaptation to high altitude hypoxia. High Alt Med Biol 9:148–157.  https://doi.org/10.1089/ham.2007.1079 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R, Diemer K, Muruganujan A, Narechania A (2003) PANTHER: a library of protein families and subfamilies indexed by function. Genome Res 13:2129–2141.  https://doi.org/10.1101/gr.772403 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Vats P, Ray K, Majumadar D, Amitabh, Joseph DA, Bayen S, Akunov A, Sarbaev A, Singh SB (2013) Changes in cardiovascular functions, lipid profile, and body composition at high altitude in two different ethnic groups. High Alt Med Biol 14:45–52.  https://doi.org/10.1089/ham.2012.1071 CrossRefPubMedGoogle Scholar
  40. Wheaton WW, Chandel NS (2011) Hypoxia. 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiology 300:C385–C393.  https://doi.org/10.1152/ajpcell.00485.2010 CrossRefGoogle Scholar
  41. Zimmerman MA, Kam I, Eltzschig H, Grenz A (2013) Biological implications of extracellular adenosine in hepatic ischemia and reperfusion injury. Am J Transplant 13:2524–2529.  https://doi.org/10.1111/ajt.12398 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Supriya Saini
    • 1
  • Praveen Vats
    • 1
    • 2
    Email author
  • Susovon Bayen
  • Priya Gaur
    • 1
  • Koushik Ray
    • 1
  • Krishna Kishore
    • 1
  • Meerim Sartmyrzaeva
    • 3
  • Almaz Akunov
    • 3
  • Abdirashit Maripov
    • 3
  • Akpay Sarybaev
    • 3
  • Bhuvnesh Kumar
    • 1
  • Shashi Bala Singh
    • 1
  1. 1.Defence Institute of Physiology and Allied SciencesTimarpurIndia
  2. 2.Endocrinology and Metabolism DivisionDefence Institute of Physiology and Allied SciencesTimarpurIndia
  3. 3.Kyrgyz Indian Mountain Biomedical Research CentreBishkekKyrgyz Republic

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