{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:55:19Z","timestamp":1789844119297,"version":"4.0.1"},"reference-count":100,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100006458","name":"Children's Hospital of Philadelphia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Sex differences influence the pathogenesis of type 1 diabetes (T1D), yet most genetic studies have treated sex as a control covariate rather than a dynamic effect modifier. Sex influences immune cell behaviour, including CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation, regulatory T cell stability, B cell autoantibody production, dendritic cell priming and monocyte\/macrophage inflammation. Underlying mechanisms include hormone\u2010responsive enhancers, X\u2010escape gene dosage and sex\u2010biassed chromatin states, intersecting with T1D\u2010associated variants to produce sex\u2010specific immune phenotypes. These insights help explain regional variation in sex ratios of T1D incidence, such as male predominance in high\u2010risk populations and female excess in low\u2010risk populations. Biological sex shapes T1D risk across multiple layers, including polygenic load; environmental exposures such as vitamin D deficiency and enteroviral infection; and sex\u2010specific hormonal, chromosomal and epigenetic influences. An integrative G\u2009\u00d7\u2009E\u2009\u00d7\u2009S (genetic\u2009\u00d7\u2009environmental\u2009\u00d7\u2009sex\u2010specific) liability\u2010threshold framework is thus supported. Clinical and translational implications include developing sex\u2010specific polygenic risk scores, biomarker panels and interventional strategies targeting pathways such as hormone signalling, vitamin D metabolism and the microbiome. Future multi\u2010omic, longitudinal studies are warranted to test genotype\u2013sex interactions, integrate sex as a core effect modifier and enable precision prevention and treatment of T1D in both males and females.\n                  <\/jats:p>","DOI":"10.1111\/dom.70124","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T05:32:06Z","timestamp":1758259926000},"page":"6857-6868","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sex as a modifier of genetic risk for type 1 diabetes"],"prefix":"10.1111","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9317-4488","authenticated-orcid":false,"given":"Hui\u2010Qi","family":"Qu","sequence":"first","affiliation":[{"name":"The Center for Applied Genomics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakon","family":"Hakonarson","sequence":"additional","affiliation":[{"name":"The Center for Applied Genomics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics, The Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Division of Human Genetics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Division of Pulmonary Medicine Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Faculty of Medicine University of Iceland  Reykjavik Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2016.02.017"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2787"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00288"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1457213"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-1785"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545942"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13391"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00880-5"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60765-5"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6906a3"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgph.0001099"},{"issue":"9","key":"e_1_2_12_13_1","first-page":"1285","article-title":"Prevalence of type 1 diabetes mellitus in Saudi Arabian children and adolescents","volume":"29","author":"Al\u2010Herbish AS","year":"2008","journal-title":"Saudi Med J"},{"key":"e_1_2_12_14_1","unstructured":"Australian Institute of Health and Welfare.How common is diabetes? Type 1 diabetes. Diabetes: Australian facts.2023. Accessed July 5 2025.https:\/\/www.aihw.gov.au\/reports\/diabetes\/diabetes\/contents\/how-common-isdiabetes\/type-1-diabetes"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-024-03107-5"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13300-023-01367-8"},{"key":"e_1_2_12_17_1","doi-asserted-by":"crossref","unstructured":"SouthA MichaelS MassicotteP.rnaturalearthdata: world vector map data from Natural Earth used in \u2018rnaturalearth\u2019 CRAN: contributed packages.2017. Accessed July 5 2025.https:\/\/cran.rproject.org\/web\/packages\/rnaturalearthdata\/","DOI":"10.32614\/CRAN.package.rnaturalearthdata"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2007.01896.x"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2010.05.011"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-017-0958-6"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.suppl_2.S52"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701652"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI180076"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1197-2"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.604000"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00794"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-023-00544-5"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.12.009"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1177\/0963689720939127"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1414"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abq2630"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13072-024-00525-x"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061577"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1313"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(22)00198-9"},{"issue":"5","key":"e_1_2_12_36_1","first-page":"567","article-title":"CD4+CD25(hi) regulatory T cells in healthy males and females mediate gender difference in the prevalence of autoimmune diseases","volume":"58","author":"Afshan G","year":"2012","journal-title":"Clin Lab"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113548"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00087"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2015.08.012"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature24265"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cophys.2018.03.010"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1450366"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00005-016-0418-6"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.20906"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2015.01.018"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2012.04.001"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm7120549"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1303400"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-020-00256-1"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-022-02227-x"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034510378683"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800352"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-4942-x"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1080\/08916934.2023.2259118"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-017-0916-x"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.156703.113"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0172681"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81894"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087377"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0439"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108485"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aap8855"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2024.09.011"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2005.08.023"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.722488"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.975858"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep12895"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2005.08.006"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng2102"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005272"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.05.016"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06010"},{"issue":"10","key":"e_1_2_12_73_1","first-page":"3762","article-title":"Androgen receptor inhibition alleviated inflammation in experimental autoimmune myocarditis by increasing autophagy in macrophages","volume":"25","author":"Ma WH","year":"2021","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602956103"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.805069"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2023.101678"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.2337\/db23-0130"},{"key":"e_1_2_12_78_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-0091"},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.4062\/biomolther.2019.071"},{"key":"e_1_2_12_80_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-14-0397"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.301608"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.128"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/mst148"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-008-1061-5"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/1216370"},{"key":"e_1_2_12_86_1","doi-asserted-by":"publisher","DOI":"10.1155\/2008\/271958"},{"key":"e_1_2_12_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(23)00122-5"},{"key":"e_1_2_12_88_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1233521"},{"key":"e_1_2_12_89_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.795596"},{"key":"e_1_2_12_90_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2019.5881"},{"key":"e_1_2_12_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17102-w"},{"key":"e_1_2_12_92_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1531390"},{"key":"e_1_2_12_93_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003500"},{"key":"e_1_2_12_94_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbinf.2024.1510352"},{"key":"e_1_2_12_95_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3920"},{"key":"e_1_2_12_96_1","doi-asserted-by":"publisher","DOI":"10.1002\/bimj.201600238"},{"key":"e_1_2_12_97_1","doi-asserted-by":"crossref","unstructured":"QuH\u2010Q OstbergK SlaterDJ et al.Sex specific genomic insights into type 1 diabetes through GWAS and single cell transcriptome analysis. medRxiv.2025. doi:10.1101\/2025.07.27.25332270","DOI":"10.1101\/2025.07.27.25332270"},{"key":"e_1_2_12_98_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aap9415"},{"key":"e_1_2_12_99_1","doi-asserted-by":"publisher","DOI":"10.1900\/RDS.2022.18.58"},{"key":"e_1_2_12_100_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-5448.2010.00686.x"},{"key":"e_1_2_12_101_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-0593"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/pdf\/10.1111\/dom.70124","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/full-xml\/10.1111\/dom.70124","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/pdf\/10.1111\/dom.70124","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T15:30:18Z","timestamp":1771342218000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/10.1111\/dom.70124"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":100,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1111\/dom.70124"],"URL":"https:\/\/doi.org\/10.1111\/dom.70124","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/DOM.70124\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70124\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70124\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70124\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.70124\/v1\/review2","asserted-by":"object"}]},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,18]]},"assertion":[{"value":"2025-07-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}