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Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negatively impacted vitamin D levels, with the high-altitude Andeans having the lowest 25-OH-D levels and the high-altitude Europeans having the lowest 1\u03b1,25-(OH)2-D levels. There was a significant interaction of genetic ancestry with altitude in the ratio of 1\u03b1,25-(OH)2-D to 25-OH-D; with the ratio being significantly lower in Europeans compared to Andeans living at high altitude. Placental gene expression accounted for as much as 50% of circulating vitamin D levels, with CYP2R1 (25-hydroxylase), CYP27B1 (1\u03b1-hydroxylase), CYP24A1 (24-hydroxylase), and LRP2 (megalin) as the major determinants of vitamin D levels. High-altitude residents had a greater correlation between circulating vitamin D levels and placental gene expression than low-altitude residents. Placental 7-dehydrocholesterol reductase and vitamin D receptor were upregulated at high altitude in both genetic-ancestry groups, while megalin and 24-hydroxylase were upregulated only in Europeans. Given that vitamin D deficiency and decreased 1\u03b1,25-(OH)2-D to 25-OH-D ratios are associated with pregnancy complications, our data support a role for high-altitude-induced vitamin D dysregulation impacting reproductive outcomes, particularly in migrants.<\/jats:p>","DOI":"10.3390\/ijms24043389","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T06:00:05Z","timestamp":1675836005000},"page":"3389","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry"],"prefix":"10.3390","volume":"24","author":[{"given":"Eugenia","family":"Mata-Greenwood","sequence":"first","affiliation":[{"name":"Lawrence D. Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans C. A.","family":"Westenburg","sequence":"additional","affiliation":[{"name":"Lawrence D. Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacy","family":"Zamudio","sequence":"additional","affiliation":[{"name":"Placental Research Group LLC, Maplewood, NJ 07040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4336-2832","authenticated-orcid":false,"given":"Nicholas P.","family":"Illsley","sequence":"additional","affiliation":[{"name":"Placental Research Group LLC, Maplewood, NJ 07040, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-8938","authenticated-orcid":false,"given":"Lubo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Lawrence D. Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3389\/fphar.2014.00149","article-title":"The Placental Pursuit for an Adequate Oxidant Balance between the Mother and the Fetus","volume":"5","author":"Herrera","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"786038","DOI":"10.3389\/fphys.2021.786038","article-title":"High Altitude Pregnancies and Vascular Dysfunction: Observations from Latin American Studies","volume":"12","author":"Herrera","year":"2021","journal-title":"Front. 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