{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:53:43Z","timestamp":1789995223979,"version":"4.0.1"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>The iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (<jats:italic toggle=\"yes\">HFE<\/jats:italic>) gene have greatest risk; yet, only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in <jats:italic toggle=\"yes\">HFE<\/jats:italic> p.C282Y and p.H63D carriers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We studied 1294 male and 1596 female UK Biobank <jats:italic toggle=\"yes\">HFE<\/jats:italic> p.C282Y homozygous participants of European ancestry with medical records up to 14\u2009years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population). Analyses were also performed in other <jats:italic toggle=\"yes\">HFE<\/jats:italic> p.C282Y\/p.H63D genotype groups.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In male p.C282Y homozygotes, a higher iron polygenic score increased the risk of liver fibrosis or cirrhosis diagnoses (odds ratio for the top 20% of iron polygenic score vs. the bottom 20%\u00a0=\u00a04.90: 95% confidence intervals, 1.63\u201314.73; <jats:italic toggle=\"yes\">p<\/jats:italic>\u00a0=\u20090.005), liver cancer, and osteoarthritis but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, the osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses and type\u20102 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y female homozygotes or in other p.C282Y\/p.H63D genotypes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>\n                                 <jats:italic toggle=\"yes\">HFE<\/jats:italic> p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population, including polygenic scores in HH screening and diagnosis, may help in estimating prognosis and treatment planning.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32575","type":"journal-article","created":{"date-parts":[[2022,5,14]],"date-time":"2022-05-14T16:14:13Z","timestamp":1652544853000},"page":"1735-1745","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":24,"title":["Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort"],"prefix":"10.1097","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3332-8454","authenticated-orcid":false,"given":"Luke C.","family":"Pilling","sequence":"first","affiliation":[{"name":"Epidemiology and Public Health Group,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,University of Exeter,Exeter,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Melzer","sequence":"additional","affiliation":[{"name":"Epidemiology and Public Health Group,University of Exeter,Exeter,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"issue":"S1","key":"hep32575-bib-0001-20250415","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/ijlh.12347","article-title":"Epidemiology and diagnostic testing for hemochromatosis and iron overload","volume":"37","year":"2015","journal-title":"Int J Lab Hematol"},{"issue":"5","key":"hep32575-bib-0002-20250415","doi-asserted-by":"crossref","first-page":"809","DOI":"10.3324\/haematol.2016.160432","article-title":"Pathophysiological consequences and benefits of HFE mutations: 20\u2009years of research","volume":"102","year":"2017","journal-title":"Haematologica"},{"issue":"12","key":"hep32575-bib-0003-20250415","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1002\/art.27712","article-title":"Musculoskeletal disease burden of hereditary hemochromatosis","volume":"62","year":"2010","journal-title":"Arthritis Rheum"},{"issue":"10045","key":"hep32575-bib-0004-20250415","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/S0140-6736(15)01315-X","article-title":"Haemochromatosis","volume":"388","year":"2016","journal-title":"Lancet"},{"issue":"20","key":"hep32575-bib-0005-20250415","article-title":"Association of hemochromatosis HFE p.C282Y homozygosity with hepatic malignancy","volume":"324","year":"2020","journal-title":"JAMA"},{"issue":"4","key":"hep32575-bib-0006-20250415","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.ajhg.2015.08.008","article-title":"Penetrance of hemochromatosis in HFE genotypes resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network","volume":"97","year":"2015","journal-title":"Am J Hum Genet"},{"issue":"3","key":"hep32575-bib-0007-20250415","first-page":"183","article-title":"Clinical penetrance of C282Y homozygous HFE haemochromatosis","volume":"25","year":"2004","journal-title":"Clin Biochem Rev"},{"issue":"1","key":"hep32575-bib-0008-20250415","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.bcmd.2015.04.001","article-title":"Hereditary hemochromatosis type 1 phenotype modifiers in Italian patients. 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