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Purpose – The endothetal Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) gene which encodes hypoxiainducible-factor-2 alpha (HIF2a) is a transcription factor that is involved in the response to hypoxia. EPAS1 has been found to have four (rs56721780, rs6756667, rs7589621, rs1868092) simple nucleotide polymorphisms (SNPs) associated with human disease. These SNPs were computationally examined with respect to changes in potential transcriptional factor binding sites (TFBS) and these changes were discussed in relation to disease and alterations in high altitude adaptation in humans. Methods -The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all the TFBS in the EPAS1 gene from 1.6 kb upstream of the transcriptional start site to 539 bps past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results – The EPAS1 SNPs in the promoter, intron two and the 3’UTR regions have previously been found to be significantly associated with disease and different levels of high-altitude hypoxia among native Tibetans. The SNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS and thereby, alter which transcriptional factors potentially regulate the EPAS1 gene such as for the glucocorticoid and mineralocorticoid nuclear receptor binding sites created by the rs7589621 rSNP EPAS1-G allele. These receptors regulate carbohydrate, protein and fat metabolism. Also the minor rs7589621 rSNP EPAS1-A creates a punitive TFBS for the FOXC TF which is an important regulator of cell viability and resistance to oxidative stress. These EPAS1 SNPs should be considered as regulatory (r) SNPs. Conclusion -The alleles of each rSNP were found to generate unique TFBS resulting in potential changes in TF EPAS1 regulation. The punitive changes in TFBS created by the four rSNPs could very well influence the significant cline in allele frequencies seen in Tibetans with increasing altitude or the haplotype association with high altitude polycythemia in male Han Chinese. These regulatory changes were discussed with respect to changes in human health that result in disease and sickness. DOI : 10.14302/issn.2326-0793.jpgr-15-889 Freely Available Online www.openaccesspub.org | JPGR CC-license DOI : 10.14302/issn.2326-0793.jpgr-15-889 Vol-1 Issue 4 Pg. no.32 Introduction: The endothetal Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) gene which encodes hypoxia-inducible -factor-2 alpha (HIF2a) is a transcription factor that is involved in the response to hypoxia. Hypoxia is a major geographical condition associated with high-altitude environments [1]. Hypoxia-inducible-factors (HIFs) are heterodimers consisting of an oxygen-labile HIFa subunit and a stable HIFb subunit [2]. During hypoxia conditions, three isoforms either HIF1a, HIF2a or HIF3a and HIF1b are activated and function as transcriptional regulators of genes involved with the hypoxia response [3-5]. Genome wide association studies (GWAS) on high -altitude adaptation have implicated several single nucleotide polymorphisms (SNPs) in the regulatory region of the EPAS1 gene which are responsible for the genetic adaptation of high-altitude hypoxia in Tibetans [6-8]. Genetic variation in the regulatory region of the EPAS1 gene may influence gene expression and contribute to changes in biological functions [9]. EPAS1 is expressed in organs that are involved in oxygen transport and metabolism, such the lung, placenta and vascular endothelium [10], and is associated with many biological processes and diseases related to metabolism [11], angiogenesis [12, 13], inflammation [14, 15] and cancer [16-18]. The EPAS1 gene maps to human chromosome 2p21 and is about 120 kb in size with a coding region consisting of 15 exons [19]. Four HIF2a SNPs (rs56721780, rs6756667, rs7589621 and rs1868092) have been significantly associated with different levels of high-altitude hypoxia among native Tibetans [20]. The rs56721780 SNP in the HIF2a promoter region has also been significantly associated with high-altitude adaptation of Tibetans [9] while the rs6756667 SNP from intron two has been significantly associated with susceptibility to acute mountain sickness in individuals unaccustomed to high altitude environments [21]. The rs1868092 SNP near the HIF2a 3’UTR has been associated with high altitude polycythemia in male Han Chinese at the Qinghai-Tibetan plateau [22]. Single nucleotide changes that affect gene expression by impacting gene regulatory sequences such as promoters, enhances, and silencers are known as regulatory SNPs (rSNPs) [23-26]. A rSNPs within a transcriptional factor binding site (TFBS) can change a transcriptional factor’s (TF) ability to bind its TFBS [2730] in which case the TF would be unable to effectively regulate its target gene [31-35]. This concept is examined for the above four HIF2a rSNPs and their allelic association with TFBS, where computation analyses [36-39] is used to identify TFBS alterations created by the HIF2a rSNPs. In this report, the rSNP associations with changes in potential TFBS are discussed with their possible relationship to disease or sickness in humans.

Computational EPAS1 rSNP Analysis, Transcriptional Factor Binding Sites And High Altitude Sickness Or Adaptation