{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T10:25:28Z","timestamp":1793701528487,"version":"4.5.1"},"reference-count":44,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000},"content-version":"unspecified","delay-in-days":10,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["NIHR301844"],"award-info":[{"award-number":["NIHR301844"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2024,2,6]]},"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      <jats:italic>HFE<\/jats:italic>\n                      haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Prospective cohort study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006\u20132010).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>451\u2009270 participants genetically similar to the 1000 Genomes European reference population, with a mean of 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main outcome measures<\/jats:title>\n                    <jats:p>\n                      Cox proportional HRs of incident clinical outcomes and mortality in those with\n                      <jats:italic>HFE<\/jats:italic>\n                      p.C282Y\/p.H63D mutations compared with those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 years to 80 years.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      12.1% of p.C282Y+\/+ males had baseline (mean age 57 years) haemochromatosis diagnoses, with a cumulative incidence of 56.4% at age 80 years. 33.1% died vs 25.4% without\n                      <jats:italic>HFE<\/jats:italic>\n                      variants (HR 1.29, 95%\u2009CI: 1.12 to 1.48, p=4.7\u00d710\n                      <jats:sup>-4<\/jats:sup>\n                      ); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there were excess delirium, dementia, and Parkinson\u2019s disease but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of women with p.C282Y+\/+ had baseline haemochromatosis diagnoses, with a cumulative incidence of 40.5% at age 80 years. There were excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95%\u2009CI: 1.27 to 2.05, p=7.8\u00d710\n                      <jats:sup>-5<\/jats:sup>\n                      ), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y\/p.H63D and p.H63D+\/+ men\u2009or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2023-081926","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T04:30:16Z","timestamp":1710304216000},"page":"e081926","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["<i>HFE<\/i>\n                    genotypes, haemochromatosis diagnosis and clinical outcomes at age 80 years: a prospective cohort study in the UK Biobank"],"prefix":"10.1136","volume":"14","author":[{"given":"Mitchell R","family":"Lucas","sequence":"first","affiliation":[{"name":"Epidemiology and Public Health Group, Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4919-9068","authenticated-orcid":false,"given":"Janice L","family":"Atkins","sequence":"additional","affiliation":[{"name":"Epidemiology and Public Health Group, Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3332-8454","authenticated-orcid":false,"given":"Luke C","family":"Pilling","sequence":"additional","affiliation":[{"name":"Epidemiology and Public Health Group, Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy D","family":"Shearman","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, South Warwickshire University NHS Foundation Trust, Warwick, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Melzer","sequence":"additional","affiliation":[{"name":"Epidemiology and Public Health Group, Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"2025121223215122000_14.3.e081926.1","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1016\/S0140-6736(23)00287-8","article-title":"Haemochromatosis","volume":"401","author":"Adams","year":"2023","journal-title":"Lancet"},{"key":"2025121223215122000_14.3.e081926.2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.vh.2019.01.010"},{"key":"2025121223215122000_14.3.e081926.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa041534"},{"key":"2025121223215122000_14.3.e081926.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)11607-2"},{"key":"2025121223215122000_14.3.e081926.5","unstructured":"Adams P . Classic hereditary hemochromatosis. National Organization for Rare Disorders; 2019. 1\u20133. 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