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

BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: ) 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. CONCLUSION: 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.