{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:38:45Z","timestamp":1786700325507,"version":"build-2736575974"},"reference-count":107,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Southern Iron Disorders Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: HFE (homeostatic iron regulator) p.S65C (rs1800730) is associated with European ancestry, although there is no comprehensive geographic study of p.S65C in Europe. Methods: We tabulated published p.S65C genotypes in European population\/control cohorts, depicted allele frequency ranges in a map, and computed correlations of p.S65C allele frequencies with latitudes and longitudes of cohort recruitment sites. Results: We identified 44 cohorts from 24 of the 44 countries of Europe. These 24 countries comprise ~62.9% of Europe\u2019s population. There were 233,528 subjects, including 38 HFE p.S65C homozygotes (~1 in 6145 subjects) and 4347 p.S65C heterozygotes (~1 in 54 subjects). Genotypes in 42 cohorts (95.5%) were consistent with Hardy\u2013Weinberg equilibrium. The median allele frequency was 0.0129 (range 0\u20130.0350). p.S65C was not reported in Bulgaria, although the allele frequency in non-Bulgarian cohorts did not differ significantly (0\/200 vs. 4423\/462,432, respectively; p = 0.2728). Allele frequency ranges (means) were 0\u20130.0100 (0.0087), 0.0101\u20130.0200 (0.0146), and \u22650.0201 (0.0253) in 7, 14, and 3 respective aggregate country cohorts (p &lt; 0.0001, all mean comparisons). The seven countries with low-range frequencies extend from north to south (Estonia to Italy). The three countries with high-range frequencies are east of ~14.1\u00b0 E (western-most border of Poland). Correlations of allele frequencies with latitudes and longitudes in 44 cohorts were not significant (p = 0.1745 and 0.6031, respectively). Conclusions: We conclude that the median HFE p.S65C allele frequency in Europe is 0.0129, allele frequencies differ between some countries, and there is no linear north-to-south or west-to-east allele frequency gradient.<\/jats:p>","DOI":"10.3390\/genes17080951","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:04:01Z","timestamp":1786698241000},"page":"951","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HFE p.S65C (rs1800730) in Europe: A Geographic Study"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2876-8276","authenticated-orcid":false,"given":"James C.","family":"Barton","sequence":"first","affiliation":[{"name":"Southern Iron Disorders Center, Birmingham, AL 35209, USA"},{"name":"Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Clayborn","family":"Barton","sequence":"additional","affiliation":[{"name":"Southern Iron Disorders Center, Birmingham, AL 35209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald T.","family":"Acton","sequence":"additional","affiliation":[{"name":"Southern Iron Disorders Center, Birmingham, AL 35209, USA"},{"name":"Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.gene.2015.10.009","article-title":"HFE gene: Structure, function, mutations, and associated iron abnormalities","volume":"574","author":"Barton","year":"2015","journal-title":"Gene"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0092-8674(00)81151-4","article-title":"Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor","volume":"93","author":"Bennett","year":"1998","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/47417","article-title":"Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor","volume":"403","author":"Bennett","year":"2000","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1006\/jmbi.1999.3252","article-title":"The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor","volume":"294","author":"West","year":"1999","journal-title":"J. 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