High-altitude (HA), the elevation above 8,000 feet, is responsible for low partial pressure of air and as a consequence reduced blood arterial oxygen saturation (SaO2) in the body. Out of many characteristic features of the HA environment, it is the hypobaric hypoxia that has the main effect on living beings and is the chief driving force for major acclimatization and adaptive processes. When exposed to this environment body undergoes various physiological changes so as to maintain the O2 availability to the tissue. The HA natives because of generations of inhabitation have acquired unique phenotypes. Compared to the HA natives, the lowland population when exposed to a similar environment reacts differentially. There are sojourners with no signs of discomfort whereas few of them experience discomfort and develop mountain disorders. Among the various mountain disorders, HA pulmonary edema (HAPE) is a unique disorder of concern especially to sojourners. It is a multi-factorial trait characterized by hypoxic pulmonary vasoconstriction, endothelial dysfunction and intra-vascular fluid retention that are contributed effectively and equally by genetic and epigenetic factors. Hence, any kind of perturbation in the regular O2 supply of the body disturbs pathways maintaining vascular and adaptive homeostasis resulting in organ dysfunction. As a consequence, the genes of these pathways become obvious candidates and hence, Apelin (APLN), Apelin receptor (APLNR), Endothelial nitric oxide synthase (NOS3) and HIF-prolyl hydroxylase 2 (EGLN1) have been elucidated in HAPE pathophysiology and adaptation. The human ethical committees of Institute of Genomics and Integrative Biology and SNM hospital have approved the study. In a comparative study of healthy highlanders (HLs) and sojourners i.e. HAPE-free controls (HAPE-f) and HAPE-patients (HAPE-p), the distribution of alleles, haplotypes, interacting genotypes, epigenetic regulations and their association with clinical and biochemical parameters provided some interesting insights. The healthy HLs and HAPE-f had significantly higher level of SaO2 compared to HAPE-p (P<0.0001). Likewise, pulmonary arterial systolic pressure (PASP) was also significantly lower in these healthy subjects. The higher SaO2 and lower PASP levels clearly signify better physical capabilities in health and vice versa in diseased state. Analysis of genotype distribution revealed significant differences in the SNPs of EGLN1, APLN, APLNR and NOS3 with respect to adaptation and HAPE. The 4.55-fold upegulated EGLN1 expression in HAPE-p (P=0.0084) when compared with HAPE-f suggested that this upregulation caused dysfunctioning of HIF1α prohibiting downstream genes from maintaining cellular O2 homeostasis. Furthermore, the risk variants rs1538664A, rs479200T, rs2486729A, rs2790879G, rs480902C, rs2486736A, and rs973252G and the respective haplotypes A-T-A-G-C-A-G, G-T-A-G-C-A-G, and G-T-G-T-C-G-A, which were over-represented in HAPE, correlated with decreased SaO2 level and increased EGLN1 expression. The 11.7 Kb long APLN sequencing showed the presence of CpG islands. The significantly higher percentage of methylation in these islands in HAPE-p seems to be responsible for downregulation of APLN expression (P>0.05). The APLN and APLNR expression was down-regulated by 3.52- and 2.35-fold in HAPE-p (P=0.003 and 0.068). Similarly, the APLN-13 levels were down-regulated in the patients compared to HAPE-f and HLs (P<0.0001). Further, analysis of risk variants APLN rs3761581G, rs2235312T and APLNR rs11544374A revealed association with decreased APLN levels and gene expression (P<0.05). As APLN-APLNR system brings its effect through activation of NOS3; therefore, the role of NOS3 was perceptible. NOS3 expression was upregulated by 5.2-fold in HLs (P=0.0015) when compared to HAPE-f and NO levels were 57.67 ±35.5 μmol/L, 73.75 ±49.9 μmol/L and 122.45 ±103.3 μmol/L in HAPE-p, HAPE-f and HLs (P<0.0001). The significant down-regulation of APLN and NO suggested the disruption of APLN-APLNR system in HAPE. Of note, the genotypes interactions between the genes depicted few best disease pre¬dicting models in HAPE (P<0.05). To conclude, the association of EGLN1 SNPs rs1538664, rs479200, rs2486729, rs2790879, rs480902, rs2486736, and rs973252 with SaO2 levels and EGLN1 expression, APLN SNPs rs3761581, rs2235312 and APLNR SNPs rs11544374 with APLN levels and APLN expression and NOS3 SNPs rs7830, rs1799983 and 4b/4a with NO levels and NOS3 expression portrayed the functional consequences of these variants at HA. In addition, this extreme environment influences the epigenetic regulation as is evident through higher methylation of APLN.