EGLN1 variants influence expression and SaO2 levels to associate with high-altitude pulmonary oedema and adaptation

Abstract 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 SaO 2 (arterial oxygen saturation) levels in the three groups. The significant inverse correlation of SaO 2 levels with PASP (pulmonary artery systolic pressure) and EGLN1 expression and the association of these polymorphisms with SaO 2 levels and EGLN1 expression contributed to uncovering the molecular mechanism underlying hypobaric hypoxic adaptation and maladaptation

Variations in angiotensin-converting enzyme gene insertion/deletion polymorphism in Indian populations of different ethnic origins

The pattern of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in the Indian population is poorly known. In order to determine the status of the polymorphism, young unrelated male army recruits were screened. The population had cultural and linguistic differences and lived in an environment that varied significantly from one region to another. Analysis of the genotype, showed higher frequency of the insertion allele in four of the five groups i.e. I allele frequency was significantly higher (P<005) in Dogras, Assamese and Kumaonese. The deletion allele frequency was comparatively higher in the fifth group that belonged to Punjab. A correlation was observed between the genotype and enzyme activity. Involvement of a single D allele in the genotype enhanced the activity up to 37.56 ± 313%. The results suggested ethnic heterogeneity with a significant gene cline with higher insertion allele frequency. Such population-based data on various polymorphisms can ultimately be exploited in pharmacogenomics

Arterial oxygen saturation under hypoxic environment of high-altitude associates with routine physical activities of natives

Per cent oxygen saturation of arterial haemoglobin levels (SaO2), a measure of hypoxemia has been analysed in the permanent residents of Ladakh. The population recognized as high-altitude controls (HAC) and high-altitudemonks (HAM), resided at the same altitude of 3600 m but differed in their routines. SaO2 was measured with a Finger-Pulse Oximeter. The HAM had 3.08% higher SaO2 (P<0.001) compared to the HAC, with mean SaO2 of 91.8°6.1% and 89.0°2.6%, respectively. Furthermore, the younger HAM also revealed an elevation of 4.55% SaO2 than the HAC of identical age (P<0.001). The HAM, who are less hypoxemic than their counterparts are physically more active, which may be a selective advantage in the extreme environment of higher altitudes

Angiotensin converting enzyme insertion allele in relation to high altitude adaptation

Angiotensin converting enzyme (ACE) gene I/D polymorphism has been associated with high altitude (HA) disorders as well as physical performance. We, however, envisage that the polymorphism may be associated with adaptation to the hypobaric hypoxia of altitude, thus facilitating physical performance. For this purpose, three unrelated adult male groups, namely (1) the Ladakhis (HLs), who reside at and above a height of 3600 m, (2) lowlanders, who migrated to Ladakh (MLLs), and (3) resident lowlanders (LLs), have been investigated. The HLs had significantly (p<0.001) greater numbers of the II homozygotes and the ID heterozygotes than the DD homozygotes, the genotype distribution being 0.46, 0.43 and 0.11 for II, ID and DD genotypes respectively. The MLLs comprised 60% II homozygotes, which was higher (p<0.001) than the HLs (46%). In the LLs, the heterozygotes were greater (p<0.001) in number than the II and DD homozygotes. The I allele frequency was 0.72 in the MLLs, 0.67 in the HLs and 0.55 in the LLs. Polymorphism study suggested that the II genotype could be associated with altitude adaptation, which might influence physical efficiency

Expression and functional activity of pro-oxidants and antioxidants in murine heart exposed to acute hypobaric hypoxia

AbstractUnder hypobaric hypoxia, antioxidant defenses of the heart are stressed by the enhanced production of ROS. Mammalian heart acclimatizes to hypoxia through altered gene expression, which we studied in murine heart exposed to 10h of acute hypobaric hypoxia (AHH), equivalent to 15000ft, using cDNA arrays. Functional classification of genes with a ⩾2-fold change revealed a number of pro-oxidants like Cyba, Xdh, Txnip, Ppp1r15b and antioxidants like Cat, Gpx1, Mt1, Mgst1. Interestingly, the protein level of Cyba, a subunit of NADPH oxidase, was markedly decreased in AHH exposed heart, suggesting the involvement of some stress response pathways. The AHH exposure also caused a significant reduction (50%) in the level of GSH (P<0.05). The present study provides a retrospective insight on the cellular antioxidant defense mechanisms under AHH

Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Genetics of pulmonary hypertension

Pulmonary hypertension (PH) is a phenotype characterized by functional and structural changes in the pulmonary vasculature, leading to increased vascular resistance. [1],[2] The World Health Organization has classified PH into five different types: arterial, venous, hypoxic, thromboembolic or miscellaneous; details are available in the main guidelines. Group I of this classification, designated as pulmonary arterial hypertension (PAH), will remain the main focus here. The pathophysiology involves signaling, endothelial dysfunction, activation of fibroblasts and smooth muscle cells, interaction between cells within the vascular wall, and the circulating cells; as a consequence plexiform lesions are formed, which is common to both idiopathic and heritable PAH but are also seen in other forms of PAH. [2],[3],[4] As the pathology of PAH in the lung is well known, this article focuses on the genetic aspects associated with the disease and is a gist of several available articles in literature

ROCK2 and MYLK variants under hypobaric hypoxic environment of high altitude associate with high altitude pulmonary edema and adaptation

Priyanka Pandey,1,2 Ghulam Mohammad,1,3 Yogendra Singh,1,2 MA Qadar Pasha1,2 1Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, Delhi, 2Department of Biotechnology, University of Pune, Ganeshkhind, Pune, Maharashtra, 3Department of Medicine, SNM Hospital, Leh, Ladakh, Jammu and Kashmir, IndiaObjective: To date, a major class of kinases, serine&ndash;threonine kinase, has been scantly investigated in stress-induced rare, fatal (if not treated early), and morbid disorder, high altitude pulmonary edema (HAPE). This study examined three major serine&ndash;threonine kinases, ROCK2, MYLK, and JNK1, along with six other genes, tyrosine hydroxylase, G-protein subunits GNA11 and GNB3, and alpha1 adrenergic receptor isoforms 1A, 1B, and 1D as candidate gene markers of HAPE and adaptation.Methods: For this, 57 variants across these nine genes were genotyped in HAPE patients (n=225), HAPE controls (n=210), and highlanders (n=259) by Sequenom MS (TOF)-based MassARRAY&reg; platform using iPLEX&trade; Gold technology. In addition, to study the gene expression, quantitative real-time polymerase chain reaction was performed in human peripheral blood mononuclear cells of the three study groups.Results: A significant association was observed for C allele (ROCK2 single-nucleotide polymorphism, rs10929728) with HAPE (P=0.03) and C, T, and A alleles (MYLK single-nucleotide polymorphisms, rs11717814, rs40305, and rs820336) with both HAPE and adaptation (P=0.001, P=0.006, and P=0.02, respectively). ROCK2 88 kb GGGTTGGT haplotype was associated with lower risk of HAPE (P=0.0009). MYLK 7 kb haplotype CTA, composed of variant alleles, was associated with higher risk of HAPE (P=0.0006) and lower association with adaptation (P=1E&ndash;06), whereas haplotype GCG, composed of wild-type alleles, was associated with lower risk of HAPE (P=0.001) and higher association with adaptation (P=1E&ndash;06). Haplotype&ndash;haplotype and gene&ndash;gene interactions demonstrated a correlation in working of ROCK2 and MYLK.Conclusion: The data suggest the association of ROCK2 with HAPE and MYLK with HAPE and adaptation in Indian population. The outcome has provided new insights into the physiology of HAPE and adaptation. Keywords: adaptation, hypobaric hypoxia, ROCK2, MYLK, high altitude pulmonary edema, SN