Downregulation of EPAS1 and EGLN1 mRNA Expression Associated With High-Altitude Adaptive Genetic Variants in Sherpa...

Sherpa highlanders exhibit remarkable tolerance to hypoxia, most likely due to genetic adaptations shaped by natural selection at high altitude. This study examined the roles of endothelial PAS domain protein 1 (EPAS1) and egl-9 family hypoxia-inducible factor 1 (EGLN1) in the genetic mechanisms underlying this adaptation.

Blood samples were collected from 56 Sherpa highlanders residing in Namche Bazaar (3440 m) and 25 non-Sherpa lowlanders in Kathmandu (1300 m). Samples were measured for serum erythropoietin (EPO) concentrations, genetic variants of EPAS1 (rs13419896:G>A; rs4953354:A>G) and EGLN1 (rs1435166:G>A; rs2153364:A>G), and mRNA expression levels of the EPAS1 and EGLN1.

Oxygen saturation (SpO₂) was significantly lower in Sherpas at high altitude than in non-Sherpas at low altitude, consistent with a hypoxic state. However, serum EPO concentrations in Sherpas were comparable to those of non-Sherpas, despite the expected hypoxia-driven stimulation of EPO production. Genotyping revealed significantly lower frequencies of the wild-type alleles of EPAS1 and EGLN1 in Sherpas compared with non-Sherpas. These genetic patterns were linked to markedly reduced mRNA expression levels of both genes in Sherpa highlanders.

High-altitude adaptive genetic variants in EPAS1 and EGLN1 are associated with reduced systemic mRNA expression of these genes and a blunted EPO response in Sherpa highlanders, suggesting transcriptional modulation of the hypoxia-induced factor pathway under chronic hypoxia. This attenuated hypoxic response manifests as the tolerance to hypoxia in Sherpa highlanders, enabling Sherpas to adapt to high-altitude hypoxia.