{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:18:24Z","timestamp":1768565904287,"version":"3.49.0"},"posted":{"date-parts":[[2023,7,24]]},"group-title":"Genetic and Genomic Medicine","reference-count":39,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,7,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Early-onset Type 1 diabetes (EOT1D) is considered a disease subtype with distinctive immunological and clinical features. While both Human Leukocyte Antigen (HLA) and non-HLA variants contribute to age at T1D diagnosis, detailed analyses of EOT1D-specific genetic determinants are still lacking. This study scrutinized the involvement of the HLA class II locus in EOT1D genetic control.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We conducted genetic association and regularized logistic regression analyses to evaluate genotypic, haplotypic and allelic variants in\n                    <jats:italic>DRB1<\/jats:italic>\n                    ,\n                    <jats:italic>DQA1<\/jats:italic>\n                    and\n                    <jats:italic>DQB1<\/jats:italic>\n                    genes in children with EOT1D (diagnosed at \u22645 years of age; n=97), individuals with later-onset disease (LaOT1D; diagnosed 8-30 years of age; n=96) and nondiabetic control subjects (n=169), in the Portuguese population.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>\n                    Analysis of EOT1D and LaOT1D unrelated patients in comparison with controls, revealed the rare DRB1*04:08-DQ8 haplotype is specifically associated with EOT1D (corrected p-value=1.4\u00d710\n                    <jats:sup>-5<\/jats:sup>\n                    ) and represents the major discriminative HLA class II genetic factor. Allelic association further indicated the DRB1*04:08 allele is a distinctive EOT1D susceptibility factor (corrected p-value=7.0\u00d710\n                    <jats:sup>-7<\/jats:sup>\n                    ). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4\u00d710\n                    <jats:sup>-2<\/jats:sup>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>\n                    This study uncovered that EOT1D holds a distinctive spectrum of HLA class II susceptibility\n                    <jats:italic>loci<\/jats:italic>\n                    , which includes risk factors overlapping with LaOT1D and discriminative genetic configurations. These findings warrant replication studies in larger multicentric settings and may impact target screening strategies and follow-up of young children with high T1D genetic risk.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>European Foundation for the Study of Diabetes, Maratona da Sa\u00fade and Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.07.23.23293034","type":"posted-content","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T14:30:17Z","timestamp":1690209017000},"source":"Crossref","is-referenced-by-count":0,"title":["The rare DRB1*04-DQ8 haplotype is the main discriminative HLA class II genetic driver of Early-Onset Type 1 Diabetes in the Portuguese population"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2479-7846","authenticated-orcid":false,"given":"Iris","family":"Caramalho","sequence":"first","affiliation":[]},{"given":"Paula","family":"Matoso","sequence":"additional","affiliation":[]},{"given":"D\u00e1rio","family":"Ligeiro","sequence":"additional","affiliation":[]},{"given":"Tiago","family":"Paix\u00e3o","sequence":"additional","affiliation":[]},{"given":"Daniel","family":"Sobral","sequence":"additional","affiliation":[]},{"given":"Ana Laura","family":"Fitas","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Limbert","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4761-614X","authenticated-orcid":false,"given":"Jocelyne","family":"Demengeot","sequence":"additional","affiliation":[]},{"given":"Carlos","family":"Penha-Gon\u00e7alves","sequence":"additional","affiliation":[]}],"member":"54368","reference":[{"key":"2023072612250700000_2023.07.23.23293034v1.1","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/S0140-6736(99)07125-1","article-title":"Variation and trends in incidence of childhood diabetes in Europe","volume":"355","year":"2000","journal-title":"The Lancet"},{"key":"2023072612250700000_2023.07.23.23293034v1.2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.2006.01925.x"},{"key":"2023072612250700000_2023.07.23.23293034v1.3","first-page":"1134","article-title":"The role of HLA class II genes in insulin-dependent diabetes 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