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The\n                      <jats:italic>DR3<\/jats:italic>\n                      -\n                      <jats:italic>DQ2<\/jats:italic>\n                      (DR3) and\n                      <jats:italic>DR4<\/jats:italic>\n                      -\n                      <jats:italic>DQ8<\/jats:italic>\n                      (DR4) haplotypes at the MHC locus associate with GADA and IAA as the first-developing autoantibodies, respectively, and can therefore be used as proxies for first autoantibody development in large cohort studies of type 1 diabetes cases and control individuals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed the first genome-wide association study of type 1 diabetes stratified by DR3 and DR4 status using 9091 type 1 diabetes cases and 14,157 control individuals from multiple cohorts. We estimated heritability and genetic correlation between type 1 diabetes with DR3 and DR4 (DR3-T1D and DR4-T1D, respectively), and with other immune and glycaemic phenotypes. We assessed heterogeneity in effects on type 1 diabetes between DR3 and DR4 individuals at known type 1 diabetes loci. We determined enrichment of type 1 diabetes heritability in DR3 and DR4 among variants in cell-type-specific\n                      <jats:italic>cis-<\/jats:italic>\n                      regulatory elements (cREs) and biological pathways, and annotated risk variants in cREs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We observed only moderate genetic correlation between DR4-T1D and DR3-T1D (\n                      <jats:italic>r<\/jats:italic>\n                      <jats:sub>g<\/jats:sub>\n                      =0.6), which was lower compared with stratifications based on age of onset and sex, and distinct patterns of genetic correlations with other autoimmune diseases. Among type 1 diabetes-associated loci, the\n                      <jats:italic>IL2<\/jats:italic>\n                      locus had significantly larger effect on type 1 diabetes in DR4 while several other loci (\n                      <jats:italic>TAGAP<\/jats:italic>\n                      ,\n                      <jats:italic>KLRG1<\/jats:italic>\n                      ) had more nominal heterogeneity. There was stronger enrichment of DR4-T1D-associated variants in T cell cREs and T cell-related pathways, while DR3-T1D-associated variants were specifically enriched in mast cell cREs and secretion-related pathways. We finally prioritised specific loci annotated in mast cells with stronger effects on type 1 diabetes in DR3 individuals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>We performed the first GWAS of type 1 diabetes stratified by DR3 and DR4 status, which revealed heterogeneity in genetic risk and biological mechanisms dependent on high-risk HLA background.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06836-w","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T15:00:19Z","timestamp":1788188419000},"page":"3580-3591","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic association stratified by HLA-DR3 and HLA-DR4 status reveals heterogeneity in pathways of progression to type 1 diabetes"],"prefix":"10.1007","volume":"69","author":[{"given":"Amber M.","family":"Luckett","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"McGrail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Murrall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily N.","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin N.","family":"Beaumont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth","family":"Hawkes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Hagopian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen S.","family":"Rich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N.","family":"Weedon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Oram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the EXE-T1D consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J.","family":"Gaulton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"6836_CR1","doi-asserted-by":"publisher","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","volume":"3","author":"A Katsarou","year":"2017","unstructured":"Katsarou A, Gudbj\u00f6rnsdottir S, Rawshani A et al (2017) Type 1 diabetes mellitus. 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The authors thank the participants, their relatives and their physicians for participating in this study. This study was supported by the University of Exeter, the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre, the NIHR Exeter Clinical Research Facility (a partnership between the University of Exeter and Royal Devon University Healthcare NHS Foundation Trust), the NIHR Oxford Biomedical Research Centre and the NIHR Birmingham Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Additional cohort acknowledgements are provided as ESM.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Summary statistics from genome-wide association studies will be made available in the GWAS catalogue upon publication. Accession numbers for existing cohorts of type 1 diabetes case and control individuals obtained from dbGaP and EGA are listed in ESM Table\n                      \n                      . Exeter cohort clinical data can be used to identify individuals and are therefore available only through collaboration to experienced teams working on approved studies examining the mechanisms, cause, diagnosis and treatment of diabetes and other beta cell disorders. Requests for collaboration will be considered by a steering committee after an application to the Genetic Beta Cell Research Bank (\n                      \n                      ). Contact by email should be directed to RAO (R.Oram@exeter.ac.uk). All requests for access to data will be responded to within 14 days.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The work in this study was funded by an endowment from the University of California to KJG, NIH R01 DK121843-01 to RAO, a JDRF strategic research agreement (3-SRA-2019-827-S-B) to RAO, a UK Medical Research Council Confidence in Concept grant to develop a type 1 diabetes GRS biochip with Randox to RAO and MNW, and research funding from Randox R&D to RAO, and a PhD studentship from Randox Laboratories Ltd to AML.","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"KJG has done consulting for Genentech, received honoraria from Pfizer and holds stock in Neurocrine biosciences, and his spouse is employed by Altos Labs, Inc. RAO has served as a consultant for Sanofi Pharmaceuticals, Provention Bio and Janssen Pharmaceuticals. RAO and MNW had a UK Medical Research Council Confidence in Concept award to develop a type 1 diabetes Genetic Risk Score biochip with Randox R&D and have ongoing research funding from Randox Laboratories Ltd. AML is funded by a PhD studentship from Randox Laboratories Ltd. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"AML and CM performed genetic and genomic analyses and wrote and reviewed the manuscript. KM, ENG, RNB and GH performed genetic and genomic analyses and reviewed the manuscript. WAH, SSR and MNW contributed to study design and reviewed the manuscript. SR contributed resources, provided interpretation of data and results, and reviewed the manuscript. KJG and RAO conceived the study, obtained funding, supervised the study and wrote and reviewed the manuscript. All authors approved the final version for publication. KJG is the guarantor of this work.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}