Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives

BMC Genetics

Soma Sarkar¹  Seema Malhotra¹  Arvind Tomar² 

[1] Defence Institute of Physiology and Allied Sciences, Ministry of Defence R&D Organization, Lucknow Road, Delhi 110054, India;Defence Research and Development Establishment, Ministry of Defence R&D Organization, Jhansi Road, Gwalior 474002, India

关键词: Indian;    Ladakh;    High altitude natives;    Adapted;    Acclimatized;    Sea level sojourners;    Polymorphism;   

Others  :  1225210
DOI  :  10.1186/s12863-015-0268-y

 received in 2015-03-17, accepted in 2015-08-28,  发布年份 2015

【 摘 要 】

Background

Sea level sojourners, on ascent to high altitude, undergo acclimatization through integrated physiological processes for defending the body against oxygen deprivation while the high altitude natives (resident population) are adapted to the prevailing hypobaric hypoxic condition through natural selection. Separating the acclimatization processes from adaptive changes and identifying genetic markers in lowlanders that may be beneficial for offsetting the high altitude hypoxic stress, although challenging, is worth investigating. We genotyped nine candidate gene polymorphisms, suggested to be relevant in high altitude environment, in sea level acclimatized sojourners and adapted natives for understanding differences/commonality between the acclimatized and the adapted cohorts at the genetic level.

Results

Statistically similar genotypic and allelic frequencies were observed between the sea level sojourners (acclimatized) and the high altitude natives (adapted) in six loci viz., EDN1 (endothelin 1) -3A/-4A VNTR, ADRB2 (beta-2 adrenergic receptor, surface) Arg16Gly (rs1042713:A > G), ADRB3 (beta-3 adrenergic receptor) Trp64Arg (rs4994:T > C), eNOS (nitric oxide synthase, endothelial) Glu298Asp (rs1799983:T > G), TH (tyrosine hydroxylase) Val81Met (rs6356:G > A) and VEGF (vascular endothelial growth factor) 963C > T (rs3025039:C > T) while SCNN1B (amiloride-sensitive sodium channel, subunit beta) Thr594Met (rs1799979:C > T) was monomorphic. Genotypic and allelic frequencies in EDN1 9465G > A (rs2071942:G > A) and ADRB2 Gln27Glu (rs1042714:G > C) were significantly different between the acclimatized sojourners and the high altitude natives with higher frequency of GG and GA genotypes of EDN1 rs2071942 and CC genotype of ADRB2 rs1042714 being observed in Ladakh natives. Mutated A allele (AA genotype) of rs2071942 and carriers of G allele (GG + GC genotypes) of rs1042714 were less favorable during acclimatization under recessive and dominant genetic models of inheritance respectively indicating thereby that GG genotype and G allele of EDN1 rs2071942 and CC genotype of ADRB2 rs1042714 conferred acclimatization benefit.

Conclusion

Sea level acclimatized individuals shared similarity with the adapted natives in certain high altitude relevant genetically based trait variation suggesting advantageous consequence as well as commonality in gene regulatory pathways in which these gene products function both during process of acclimatization and adaptation in high altitude environment.

【 授权许可】

   
2015 Tomar et al.

【 参考文献 】

• [1]West JB, Schoene RB, Milledge JS. High altitude medicine and physiology. Hodder Arnold, London; 2007.
• [2]Fulco CS, Rock PB, Cymerman A. Maximal and submaximal exercise performance at altitude. Aviat Space Environ Med. 1998; 69:793-801.
• [3]Muza SR, Fulco CS, Cymerman A. Altitude Acclimatization guide. US Army Research Institute of Environmental Medicare. Report No TN04-05. 2004.
• [4]McSherry PE. Effect of altitude on physiological performance: a statistical analysis using results of International football game. BMI. 2007; 335:1278-81.
• [5]Rupert JL, Hochachka PW. Genetic approaches to understanding human adaptation to altitude in the Andes. J Exp Biol. 2001; 204:3151-60.
• [6]Beall CM. Two routes to functional adaptation: Tibetan and Andean high altitude natives. Proc Natl Acad Sci (USA). 2007; 104:8655-60.
• [7]Beall CM. Andean, Tibetan and Ethiopian patterns of adaptation to high-altitude hypoxia. Integr Comp Biol. 2006; 46:18-24.
• [8]Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, et al. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A. 2010;107:11459–64.
• [9]Dua GL, SenGupta J. A study of physical work capacity of sea level residents on prolonged stay at high altitude and comparison with high altitude native residents. Ind J Physiol Pharmacol. 1980; 24:15-24.
• [10]Lakhera SC, Kain TC. Comparison of pulmonary function amongst Ladakhi, Delhi, Vanvasi and Siddi boy athletes. Ind J Physiol Pharmacol. 1995; 39:255-8.
• [11]Sinha S, Ray US, Tomar OS, Singh SN. Different adaptation patterns of antioxidant system in natives and sojourners at high altitude. Respir Physiol Neurobiol. 2009; 167:255-60.
• [12]Bhagi S, Srivastava S, Sarkar S, Singh SB. Distribution of performance-related gene polymorphisms (ACTN3 R577X and ACE ID) in different ethnic groups of the Indian Army. J Basic Clin Physiol Pharmacol. 2013; 24:225-34.
• [13]Rigat B, Hubert C, Alhene-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensinI-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990; 86:1343-6.
• [14]Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51:197–205.
• [15]Droma Y, Hanaoka M, Basnyat B, Arjyal A, Neupane P, Pandit A, et al. Adaptation to high altitude in Sherpas: association with the insertion/deletion polymorphism in the Angiotensin-converting enzyme gene. Wilderness Environ Med. 2008;19:22–9.
• [16]Bigham AW, Kiyamu M, Leon-Velarde F, Parra EJ, Rivera-Ch M, Shriver MD, et al. Angiotensin converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quencha. High Alt Med Biol. 2008;9:167–78.
• [17]Bhagi S, Srivastava S, Tomar A, Singh SB, Sarkar S. Positive association of D allele of ACE gene with high altitude pulmonary edema in Indian population. Wilderness Environ Med. 2015; 26:124-32.
• [18]Colice GL, Ramirez G. Effect of hypoxemia on the renin-angiotensin-aldosterone system in humans. J Appl Physiol. 1985; 58:724-30.
• [19]Jeunemaitre X, Charru A, Chatellier G, Dumont C, Sassano P, Soubrier F, et al. M235T variant of the human angiotensinogen gene in unselected hypertensive patients. J Hypertens. 1993;11:80–1.
• [20]Srivastava S, Bhagi S, Kumari B, Chandra K, Sarkar S, Ashraf MZ. Association of polymorphisms in angiotensin and aldosterone synthase genes of the renin-angiotensin-aldosterone system with high-altitude pulmonary edema. J Renin Angiotensin Aldosterone System. 2011; 13:155-60.
• [21]Ahsan A, Norboo T, Baig M, Pasha M. Simultaneous selection of the wild type genotypes of the G894T and 4B/4A polymorphisms of NOS3 associate with high altitude adaptation. Ann Hum Genet. 2005; 69:260-7.
• [22]Erzurum SC, Ghosh S, Janocha AJ, Xu W, Bauer S, Bryan NS, et al. Higher blood flow and circulating NO products offset high altitude hypoxia among Tibetans. Proc Natl Acad Sci U S A. 2007;104:17593–8.
• [23]Duplain H, Sartori C, Lepori M, Egli M, Alleman Y, Nicod P, et al. Exhaled nitric oxide in high altitude pulmonary edema: role in the regulation of pulmonary vascular tone and evidence for a role against inflammation. Am J Crit Care Med. 2000;162:221–4.
• [24]Rajput C, Najib S, Norboo T, Afrin F, Pasha M. Endothelin-1 gene variants and levels associate with adaptation to hypobaric hypoxia in high altitude natives. Biochem Biophys Res Commun. 2006; 341:1218-24.
• [25]Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA. Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, and p300/CBP. J Biol Chem. 2001; 276:12645-53.
• [26]Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, et al. Role of endothelin-1 in exposure to high altitude: acute mountain sickness and endothelin-1 (ACME-1) study. Circulation. 2006;114:1410–6.
• [27]Goerre S, Wenk M, Bartsch P, Luscher TF, Niroomand F, Hohenhaus E, et al. Endothelin-1 in pulmonary hypertension associated with high-altitude exposure. Circulation. 1995;91:359–64.
• [28]Sartori C, Vollenweider L, Loffler BM, Delabays A, Nicod P, Bartsch P, et al. Exaggerated endothelin release in high-altitude pulmonary edema. Circulation. 1999;99:2665–8.
• [29]Horgan MJ, Pinheiro JM, Malik AB. Mechanism of endothelin-1-induced pulmonary vasoconstriction. Circ Res. 1991; 69:157-64.
• [30]Hu J, Discher DJ, Bishopric NH, Webster KA. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun. 1998; 245:894-9.
• [31]Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic visualization of beta adrenoceptor subtypes in human lung. Am Rev Respir Dis. 1985; 132:541-7.
• [32]Sakuma T, Folkesson HG, Suzuki S, Okaniwa G, Fujimura S, Matthay MA. Beta-adrenergic agonist stimulated alveolar fluid clearance in ex vivo human and rat lungs. Am J Respir Crit Care Med. 1997; 155:506-12.
• [33]Mazzeo RS, Reeves JT. Adrenergic contribution during acclimatization to high altitude: perspectives from Pikes Peak. Exerc Sport Sci Rev. 2003; 31:13-8.
• [34]Cockcroft JR, Gazis AG, Cross DJ, Wheatley A, Dewar J, Hall IP, et al. Β2-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension. 2000;36:371–5.
• [35]Dishy V, Sofowora GG, Xie HG, Kim RB, Byrne DW, Stein CM, et al. The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med. 2001;345:1030–5.
• [36]Schafer JA. Abnormal regulation of ENAC: syndromes of salt retention and salt wasting by the collecting duct. Am J Physiol Renal. 2002; 283:F221-35.
• [37]Bertorello AM, Ridge KM, Chibalin AV, Katz AI, Sznajder JI. Isoproterenol increases Na + -K + -ATPase activity by membrane insertion of alpha-subunits in lung alveolar cells. Am J Physiol Lung Cell Mol Physiol. 1999; 276:L20-7.
• [38]Czyzyk-Krzeska MF, Bayliss DA, Lawson EE, Millhorn DE. Regulation of tyrosine hydroxylase gene expression in the rat carotid body by hypoxia. J Neurochem. 1992; 58:1538-46.
• [39]Pepin JL, Levy P, Garcin A, Feuerstein C, Savasta M. Effect of long-term hypoxia on tyrosine hydroxylase protein content in catecholaminergic rat brain stem areas: a quantitative autoradiographic study. Brain Res. 1996; 733:1-8.
• [40]Roux JC, Pequignot JM, Dumas S, Pascual O, Ghilini G, Pequignot J, et al. O2-sensing after carotid chemodenervation: hypoxic ventilatory responsiveness and upregulation of tyrosine hydroxylase mRNA in brainstem catecholaminergic cells. Eur J Neurosci. 2000;12:3181–90.
• [41]Walter R, Maggiorini M, Scherrer U. Effects of high-altitude exposure on vascular endothelial growth factor levels in man. Eur J Appl Physiol. 2001; 85:113-7.
• [42]Dorward DA, Thompson AA, Baillie JK, MacDougall M, Hirani N. Change in plasma vascular endothelial growth factor during onset and recovery from acute mountain sickness. Respir Med. 2007; 101:587-94.
• [43]Hacket PH, Oelz O. The Lake Luoise consensus on the definition and quantitation of altitude illness. In: Sutton J, Coates G, Houston C, editors. Hypoxia and Mountain Medicines. Burlington: Queen City Printers; 1992. p. 307–20.
• [44]Bhasin MK. Genetics of castes and tribes of India. Indian population milieu. Int J Hum Genet. 2006; 6:233-74.
• [45]Snyder EM, Beck KC, Turner ST, Hoffman EA, Joyner MJ, Johnson BD. Genetic variation of the β2-adrenergic receptor is associated with differences in lung fluid accumulation in humans. J App Physiol. 2007; 102:2172-8.
• [46]Wang P, Koeehle MS, Rupert JL. Common haplotypes in the beta-2 adrenergic receptor gene are not associated with acute mountain sickness susceptibility in Nepalese. High Alt Med Biol. 2007; 8:206-12.
• [47]Stobdan T, Kumar R, Mohammad G, Thinlas T, Norboo T, Iqbal M, et al. Probable role of beta2-adrenergic receptor gene haplotypes in high-altitude pulmonary edema. Respirology. 2010;15:651–8.
• [48]Ahsan A, Charu R, Pasha M, Norboo T, Afrin F, Baig M. eNOS allelic variants at the same locus associate with HAPE and adaptation. Thorax. 2004; 59:1000-2.
• [49]Beall CM, Laskowski D, Strohl KP, Soria R, Villena M, Vargas E, et al. Pulmonary nitric oxide in mountain dwellers. Nature. 2001;414:411–2.
• [50]Wang P, Ha AY, Kidd KK, Koehle MS, Rupert JL. 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. 2010; 11:27-30.
• [51]Droma Y, Hanaoka M, Basnyat B, Arjyal A, Neupane P, Pandit A, et al. Genetic contribution of the endothelial nitric oxide synthase gene to high altitude adaptation in Sherpas. High Alt Med Biol. 2006;7:209–20.
• [52]Droma Y, Hanaoka M, Ota M, Katsuyama Y, Koizumi T, Fujimoto K, et al. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high altitude pulmonary edema. Circulation. 2002;106:826–30.
• [53]Wang QQ, Yu L, Huang GR, Zhang L, Liu YQ, Wang TW, et al. Polymorphisms of angiotensin converting enzyme and nitric oxide synthase 3 genes as risk factors of high-altitude pulmonary edema: a case–control study and meta-analysis. Tohoku J Exp Med. 2013;229:255–66.
• [54]Ding H, Liu Q, Hua M, Ding M, Du H, Zhang W, et al. Associations between vascular endothelial growth factor gene polymorphisms and susceptibility to acute mountain sickness. J Int Med Res. 2012;40:2135–44.
• [55]Matsuzawa Y, Fujimoto K, Kobayashi T, Namushi NR, Harada K, Kohno H, et al. Blunted hypoxic ventilatory drive in subjects susceptible to high altitude pulmonary edema. J Appl Physiol. 1989;66:1152–7.
• [56]Hanaoka M, Droma Y, Hotta J, Matsuzawa Y, Kobayashi T, Kubo K, et al. Polymorphisms of the tyrosine hydroxylase gene in subjects susceptible to high-altitude pulmonary edema. Chest. 2003;123:54–8.
• [57]Ali Z, Mishra A, Kumar R, Alam P, Pandey P, Ram RB, et al. Interactions among vascular-tone modulators contribute to high altitude pulmonary edema and augmented vasoreactivity in highlanders. PLoS ONE. 2012;7:e44049.
• [58]Charu R, Stobdan T, Ram RB, Khan AP, Pasha MAQ, Norboo T, et al. Susceptibility to high-altitude pulmonary oedema: role of ACE and ET-1 polymorphisms. Thorax. 2006;61:1011–2.
• [59]Sharma M, Singh SB, Sarkar S. Genome wide expression analysis suggests perturbation of vascular homeostasis during high altitude pulmonary edema. PLoS ONE. 2014; 9:e85902.
• [60]Agachan B, Ergen HA, Isbir CS, Ozturk O, Farsak B, Zeybek U. Effects of endothelin (G8002A) gene polymorphism on serum endothelin levels in Turkish coronary artery disease patients. Adv Mol Med. 2005; 1:125-8.
• [61]Taylor MR, Slavov D, Humphrey K, Zhao L, Cockroft J, Zhu X, et al. Pharmacogenetic effect of an endothelin-1 haplotype on response to bucindolol therapy in chronic heart failure. Pharmacogenet Genomics. 2009;19:35–43.
• [62]Diefenbach K, Arjomand-Nahad F, Meisel C, Feitze I, Stangl K, Roots I, et al. Systematic analysis of sequence variability of the endothelin-1 gene: a prerequisite for association studies. Genet Test. 2006;10:163–8.
• [63]Moore LG, Shriver M, Bemis L, Hickler B, Wilson M, Brutsaert T, et al. Maternal adaptation to high-altitude pregnancy: an experiment of nature - a review. Placenta. 2004;25:S60–71.
• [64]Bulow R, Fitzner B, Sparmann G, Emmrich J, Liebe S, Jaster R. Antifibrogenic effects of histone deacetylase inhibitors on pancreatic stellate cells. Biochem Pharmacol. 2007; 74:1747-57.
• [65]Yeligar S, Tsukamoto H, Kalra VK. Ethanol-induced expression of ET-1 and ET-BR in liver sinusoidal endothelial cells and human endothelial cells involves hypoxia-inducible factor-1 alpha and micro rNA-199. J Immunol. 2009; 183:5232-43.
• [66]Vallender TW, Lahn BT. Localized methylation in the key regulator gene endothelin-1 is associated with cell type-specific transcriptional silencing. FEBS Lett. 2006; 580:4560-6.
• [67]Litonjua AA, Gong L, Duan QL, Shin J, Moore MJ, Weiss ST, et al. Very important pharmacogene summary ADRB2. Pharmacogenet Genomics. 2010;20:64–9.
• [68]Abecasis GR, Auton A, Brooks LD, De Pristo MA, Durbin RM et al.. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491:56-65.
• [69]Rupert JL, Monsalve MV, Devine DV, Hochachka PW. Beta2-adrenergic receptor allele frequencies in the Quechua, a high altitude native population. Ann Hum Genet. 2000; 64:135-43.
• [70]Aldashev AA. Gene polymorphisms and high altitude pulmonary hypertension. In: Problems of High Altitude Medicine and Biology. Aldashev AA, Naeije R, editors. New York, Springer; 2007: p.151-68.
• [71]Negi PC, Bhardwaj R, Kandoria A, Asotra S, Ganju N, Marwaha R, et al. Epidemiological study of hypertension in natives of Spiti Valley in Himalayas and impact of hypobaric hypoxemia. a cross-sectional study. J Assoc Physicians Ind. 2012;60:21–5.
• [72]Liggett SB, Raymond J. Pharmacology and molecular biology of adrenergic receptors. Baillieres Clin Endocrinol Metab. 1993; 7:279-306.
• [73]McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics. 2010; 26:2069-70.
• [74]Stow LR, Jacobs ME, Wingo CS, Cain BD. Endothelin-1 gene regulation. FASEB J. 2011; 25:16-28.
• [75]FSPLICE:. http://www. softberry.com/berry.phtml?topic=fsplice&group=programs&subgroups=gfind webcite
• [76]Genetic landscape of the people of India: a canvas for disease gene exploration. J Genet. 2008; 87:3-20.
• [77]Bigham AW, Mao X, Mei R, Brutsaert T, Wilson MJ, Julian CG, et al. Identifying positive selection candidate loci for high altitude adaptation in Andean populations. Hum Genomics. 2009;4:79–90.
• [78]Bigham AW, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, et al. Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet. 2010;6:e1001116.
• [79]Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, et al. Genetic evidence for high-altitude adaptation in Tibet. Science. 2010;329:72–5.
• [80]Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, et al. Sequencing of 50 human exomes reveals adaptation to high altitude. Science. 2010;329:75–9.
• [81]Xu S, Li S, Yang Y, Tan J, Lou H, Jin W, et al. A genome -wide search for signals of high altitude adaptation in Tibetans. Mol Biol Evol. 2011;28:1003–11.
• [82]Scheinfeldt LB, Soi S, Thompson S, Ranciaro A, Woldemeskel D, Beggs W, et al. Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol. 2012;13:R1.
• [83]Malacrida S, Katsuyama Y, Droma Y, Basnyat B, Angelini C, Ota M, et al. Association between human polymorphic DNA markers and hypoxia adaptation in Sherpa detected by a preliminary genome scan. Ann Hum Genet. 2007;71:630–8.
• [84]Goebel T, Waters MR, O’Rourke DH. The late Pleistocene dispersal of modern humans in the Americas. Science. 2008; 319:1497-502.
• [85]Prasad P, Thelma BK. Normative Genetic Profiles of RAAS pathway gene polymorphisms in North and South Indian populations. Hum Biol. 2007; 79:241-54.
• [86]Tiwari AK, Punia S, Juyal RC, Thelma BK. Genetic profiling of genes from the oxidative stress pathway among North and South Indians. Hum Biol. 2008; 80:161-79.
• [87]Juyal G, Mondal M, Luisi P, Laayouni H, Sood A, Midha V, et al. Population and genomic lessons from genetic analysis of two Indian populations. Hum Genet. 2014;133:1273–87.
• [88]Wilmore JH, Costill DL. Physiology of Sport and Exercise: 3rd Edition. Human Kinetics, Champaign, IL; 2005.
• [89]Masschelein E, Puype J, Broos S, van Thienen R, Deldicque L, Lambrechts D, et al. A genetic predisposition score associates with reduced aerobic capacity in response to acute normobaric hypoxia in lowlanders. High Alt Med Biol. 2015;16:34–42.