{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:43:40Z","timestamp":1792640620279,"version":"4.5.0"},"reference-count":45,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T00:00:00Z","timestamp":1770508800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T00:00:00Z","timestamp":1770508800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Human Genetics"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>endothelial PAS domain protein 1<\/jats:italic>\n                      (\n                      <jats:italic>EPAS1<\/jats:italic>\n                      ) and\n                      <jats:italic>egl\u20109 family hypoxia\u2010inducible factor 1<\/jats:italic>\n                      (\n                      <jats:italic>EGLN1<\/jats:italic>\n                      ) in the genetic mechanisms underlying this adaptation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Blood samples were collected from 56 Sherpa highlanders residing in Namche Bazaar (3440 m) and 25 non\u2010Sherpa lowlanders in Kathmandu (1300 m). Samples were measured for serum erythropoietin (EPO) concentrations, genetic variants of\n                      <jats:italic>EPAS1<\/jats:italic>\n                      (rs13419896:G&gt;A; rs4953354:A&gt;G) and\n                      <jats:italic>EGLN1<\/jats:italic>\n                      (rs1435166:G&gt;A; rs2153364:A&gt;G), and mRNA expression levels of the\n                      <jats:italic>EPAS1<\/jats:italic>\n                      and\n                      <jats:italic>EGLN1<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Oxygen saturation (SpO\n                      <jats:sub>2<\/jats:sub>\n                      ) was significantly lower in Sherpas at high altitude than in non\u2010Sherpas at low altitude, consistent with a hypoxic state. However, serum EPO concentrations in Sherpas were comparable to those of non\u2010Sherpas, despite the expected hypoxia\u2010driven stimulation of EPO production. Genotyping revealed significantly lower frequencies of the wild\u2010type alleles of\n                      <jats:italic>EPAS1<\/jats:italic>\n                      and\n                      <jats:italic>EGLN1<\/jats:italic>\n                      in Sherpas compared with non\u2010Sherpas. These genetic patterns were linked to markedly reduced mRNA expression levels of both genes in Sherpa highlanders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      High\u2010altitude adaptive genetic variants in\n                      <jats:italic>EPAS1<\/jats:italic>\n                      and\n                      <jats:italic>EGLN1<\/jats:italic>\n                      are associated with reduced systemic mRNA expression of these genes and a blunted EPO response in Sherpa highlanders, suggesting transcriptional modulation of the hypoxia\u2010induced factor pathway under chronic hypoxia. This attenuated hypoxic response manifests as the tolerance to hypoxia in Sherpa highlanders, enabling Sherpas to adapt to high\u2010altitude hypoxia.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ahg.70034","type":"journal-article","created":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T12:05:46Z","timestamp":1770552346000},"page":"202-214","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Downregulation of\n                    <i>EPAS1<\/i>\n                    and\n                    <i>EGLN1<\/i>\n                    mRNA Expression Associated With High\u2010Altitude Adaptive Genetic Variants in Sherpa Highlanders"],"prefix":"10.1111","volume":"90","author":[{"given":"Yunden","family":"Droma","sequence":"first","affiliation":[{"name":"First Department of Medicine Shinshu University School of Medicine  Matsumoto 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