EGLN1 [encoding HIF (hypoxia-inducible factor)-prolyl hydroxylase 2] plays a pivotal role in the HIF pathway and has emerged as one of the most intriguing genes with respect to physiology at HA (high altitude). EGLN1, being an actual oxygen sensor, appears to have a potential role in the functional adaptation to the hypobaric hypoxic environment. In the present study, we screened 30 polymorphisms of EGLN1, evaluated its gene expression and performed association analyses. In addition, the role of allelic variants in altering TF (transcription factor)-binding sites and consequently the replacement of TFs at these loci was also investigated. The study was performed in 250 HAPE-p [HAPE (HA pulmonary oedema)-patients], 210 HAPE-f (HAPE-free controls) and 430 HLs (healthy Ladakhi highland natives). The genotypes of seven polymorphisms, rs1538664, rs479200, rs2486729, rs2790879, rs480902, rs2486736 and rs973252, differed significantly between HAPE-p and HAPE-f (P<0.008). The genotypes AA, TT, AA, GG, CC, AA and GG of rs1538664, rs479200, rs2486729, rs2790879, rs480902, rs2486736 and rs973252, prevalent in HAPE-p, were identified as risk genotypes and their counterpart homozygotes, prevalent in HLs, were identified as protective. EGLN1 expression was up-regulated 4.56-fold in HAPE-p (P=0.0084). The risk genotypes, their haplotypes and interacting genotypes were associated with up-regulated EGLN1 expression (P<0.05). Similarly, regression analysis showed that the risk alleles and susceptible haplotypes were associated with decreased SaO2 (arterial oxygen saturation) levels in the three groups. The significant inverse correlation of SaO2 levels with PASP (pulmonary artery systolic pressure) and EGLN1 expression and the association of these polymorphisms with SaO2 levels and EGLN1 expression contributed to uncovering the molecular mechanism underlying hypobaric hypoxic adaptation and maladaptation.
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Research Article|
December 13 2012
EGLN1 variants influence expression and SaO2 levels to associate with high-altitude pulmonary oedema and adaptation
Aastha Mishra;
Aastha Mishra
*Institute of Genomics and Integrative Biology, Delhi, India
†Department of Biotechnology, University of Pune, Pune, India
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Ghulam Mohammad;
Ghulam Mohammad
‡Department of Medicine, Sonam Norboo Memorial Hospital, Leh, Ladakh, Jammu & Kashmir, India
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Tashi Thinlas;
Tashi Thinlas
‡Department of Medicine, Sonam Norboo Memorial Hospital, Leh, Ladakh, Jammu & Kashmir, India
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M. A. Qadar Pasha
*Institute of Genomics and Integrative Biology, Delhi, India
Correspondence: Dr M. A. Qadar Pasha (email qpasha@igib.res.in).
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Publisher: Portland Press Ltd
Received:
July 10 2012
Revision Received:
September 11 2012
Accepted:
November 07 2012
Accepted Manuscript online:
November 07 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 124 (7): 479–489.
Article history
Received:
July 10 2012
Revision Received:
September 11 2012
Accepted:
November 07 2012
Accepted Manuscript online:
November 07 2012
Citation
Aastha Mishra, Ghulam Mohammad, Tashi Thinlas, M. A. Qadar Pasha; EGLN1 variants influence expression and SaO2 levels to associate with high-altitude pulmonary oedema and adaptation. Clin Sci (Lond) 1 April 2013; 124 (7): 479–489. doi: https://doi.org/10.1042/CS20120371
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