{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T17:42:01Z","timestamp":1757612521171,"version":"3.44.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Although interleukin receptors have been implicated in various autoimmune diseases, their role in type 1 diabetes (T1D) remains underexplored and occasionally inconsistent. To evaluate the impact of polymorphisms in genes encoding the interleukin receptors IL-21R and IL-17RA on T1D susceptibility and other autoimmune manifestations, we analyzed 639 patients with T1D and 653 healthy controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Selected variants in IL17RA (n=4), IL21R (n=4), were genotyped using the VeraCode GoldenGate assay (Illumina, USA). Autoantibodies were assessed by radioimmunoassay, ELISA, and a radiolabeled iodine receptor assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two IL17RA variants were significantly associated with T1D: the rs2241049G allele was linked to increased susceptibility (OR=1.42; <jats:italic>p<\/jats:italic>=0.005), whereas the rs879577A allele was related to protection (OR=0.61; <jats:italic>p<\/jats:italic>=0.021) and a reduced frequency of anti-tyrosine phosphatase (anti-IA2) autoantibody (OR= 0.52; <jats:italic>p<\/jats:italic>=0.010). Additionally, the rs5748863G allele was also associated with a lower frequency of anti-IA2 positivity (OR=0.52; <jats:italic>p<\/jats:italic>=0.010). Among IL21R variants, only rs7199138C was associated with an increased risk of T1D (OR=1.33; <jats:italic>p<\/jats:italic>=0.018). Moreover, rs2214537G and rs2285452A were linked to a reduced frequency of anti-parietal cell (OR=0.24; <jats:italic>p<\/jats:italic>&amp;lt;0.001) and anti-endomysium (OR=0.17; <jats:italic>p<\/jats:italic>=0.025) autoantibodies, respectively. In contrast, rs2285452A and rs3093315T were related to a higher frequency of anti-thyroperoxidase (OR=2.38; <jats:italic>p<\/jats:italic>=0.028) and TSH receptor (TRAb) autoantibodies (OR=5.90; <jats:italic>p<\/jats:italic>=0.024), respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings suggest that polymorphisms in IL17RA and IL21R genes may contribute to T1D pathogenesis and modulate the presence of pancreatic and extra-pancreatic autoantibodies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1620509","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T13:20:02Z","timestamp":1756992002000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["IL17RA and IL21R polymorphisms influence type 1 diabetes predisposition and autoimmune phenotypes"],"prefix":"10.3389","volume":"16","author":[{"given":"Cintia","family":"Semzezem","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karla Fabiana Brasil","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aritania Sousa","family":"Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pauline","family":"Brochet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindiane Gomes","family":"Crisostomo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcia Regina Soares","family":"Correia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda Farage","family":"Frade-Barros","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luciano Abreu","family":"Brito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Rita","family":"Passos-Bueno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe","family":"Chevillard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edecio","family":"Cunha-Neto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Elizabeth Rossi","family":"da Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/S0140-6736(13)60591-7","article-title":"Type 1 diabetes","volume":"383","author":"Atkinson","year":"2014","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1590\/s0004-27302008000200004","article-title":"Marcadores gen\u00e9ticos e auto-imunes do diabetes melito tipo 1: da teoria para a pr\u00e1tica [Genetic and humoral autoimmunity markers of type 1 diabetes: from theory to practice","volume":"52","author":"Silva","year":"2008","journal-title":"Arq Bras Endocrinol Metabol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-012-9673-4","article-title":"Autoantibodies and high-risk HLA susceptibility markers in first-degree relatives of Brazilian patients with type 1 diabetes mellitus: a progression to disease based study","volume":"32","author":"Alves","year":"2012","journal-title":"J\u00a0Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.02.103","article-title":"The potential pathogenic role of IL-17\/Th17 cells in both type 1 and type 2 diabetes mellitus","volume":"101","author":"Abdel-Moneim","year":"2018","journal-title":"BioMed Pharmacother"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-019-00733-8","article-title":"The pathogenicity of Th17 cells in autoimmune diseases","volume":"41","author":"Yasuda","year":"2019","journal-title":"Semin Immunopathol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4110\/in.2024.24.e2","article-title":"IL-17 and IL-21: their immunobiology and therapeutic potentials","volume":"24","author":"Koh","year":"2024","journal-title":"Immune Netw"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6823-13-26","article-title":"Polymorphisms of interleukin-21 and interleukin-21-receptor genes confer risk for autoimmune thyroid diseases","volume":"13","author":"Zhang","year":"2013","journal-title":"BMC Endocr Disord"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/6600264","article-title":"Lubberts E. 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