High altitude (HA, 2500 m above sea level) has a unique exposome characterized by the low partial pressure of oxygen. Exposure to such harsh environmental conditions results in a reversible process of physiological acclimatization to optimize the supply of oxygen to tissues. Some sojourners show better tolerance to hypoxia but in some, hypoxia can trigger a maladaptive response leading to HA illnesses. High altitude pulmonary edema (HAPE) is one such acute HA illness that develops upon rapid ascent to altitudes above 2500 m in otherwise healthy individuals. Adopting a case-control design comprising HAPE patients and healthy controls visiting HA under similar conditions offers a natural laboratory setup to study hypoxia modulated cellular response. The acquired observations can be applied to several cancer, cardiovascular and respiratory diseases where hypoxia responses are explicitly involved. The lack of oxygen elicits hypoxia inducible factor (HIF)-dependent and HIF-independent signaling pathways that induce changes to chromatin that may further contribute to the transcriptional response to hypoxia stimulus. Our study not only identified the effect of genetic alterations in a gene encoding an enzyme, prolyl hydroxylase domain protein 2 (PHD2) but also underlined a functional association between its genetic variations and expression under hypobaric hypoxic environment. The genetic setup appeared relevant in the regulation of the genes through the differential distribution of their variant alleles and the respective transcription factors in the healthy and susceptible subjects. We were also able to identify the potential regulatory variants in the methylation region of the gene that may get influenced by the differential methylation of the CpG island observed under HA settings. The correlation studies of gene variants and methylation distribution with plasma PHD2 level and blood arterial oxygen saturation levels further emphasized the functionality of the risk markers.