{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:44:44Z","timestamp":1790995484846,"version":"4.1.0"},"reference-count":41,"publisher":"American Diabetes Association","issue":"2","license":[{"start":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T00:00:00Z","timestamp":1733184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100017618","name":"Division of Diabetes, Endocrinology, and Metabolic Diseases","doi-asserted-by":"publisher","award":["DK120429"],"award-info":[{"award-number":["DK120429"]}],"id":[{"id":"10.13039\/100017618","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017618","name":"Division of Diabetes, Endocrinology, and Metabolic Diseases","doi-asserted-by":"publisher","award":["DK122607"],"award-info":[{"award-number":["DK122607"]}],"id":[{"id":"10.13039\/100017618","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,2,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>More than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3\/DR4 and improve prediction of T1D risk in these individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>We performed T1D association and fine-mapping analyses in 12,316 non-DR3\/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3\/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3\/DR4 and DR3\/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3\/DR4 and compared with an existing T1D GRS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>A total of 18 T1D risk variants in non-DR3\/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3\/DR4 status, and non-DR3\/DR4 T1D had evidence for a greater polygenic burden. T1D-associated variants in non-DR3\/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and \u03b2-cells and depleted in T cells compared with DR3\/DR4. A non-DR3\/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3\/DR4 T1D from no diabetes (area under the curve 0.867; P = 7.48\u2009\u00d7\u200910\u221232) and type 2 diabetes (0.907; P = 4.94\u2009\u00d7\u200910\u221244).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>In total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3\/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc24-1251","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T15:24:56Z","timestamp":1733239496000},"page":"202-211","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":19,"title":["Genetic Discovery and Risk Prediction for Type 1 Diabetes in Individuals Without High-Risk HLA-DR3\/DR4 Haplotypes"],"prefix":"10.2337","volume":"48","author":[{"given":"Carolyn","family":"McGrail","sequence":"first","affiliation":[{"name":"1Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Chiou","sequence":"additional","affiliation":[{"name":"1Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Elgamal","sequence":"additional","affiliation":[{"name":"1Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9496-3796","authenticated-orcid":false,"given":"Amber M.","family":"Luckett","sequence":"additional","affiliation":[{"name":"2University of Exeter College of Medicine 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