IL17RA and IL21R Polymorphisms Influence Type 1 Diabetes Predisposition and Autoimmune Phenotypes

Cintia Semzezem¹Karla Fabiana Brasil Gomes¹Aritania Sousa Santos¹Pauline Brochet²Marcia Regina Correia Soares³Amanda Farade Frade-Barros⁴Luciano da Silva Brito⁵Maria Rita Passos-Bueno⁵Christophe Chevillard⁶Edecio Cunha-Neto⁷Maria Elizabeth Rossi Silva^1*

• ¹Laboratório de Carboidratos e Radioimunoensaios - LIM 18, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
• ²Parc Scientifique de Luminy, INSERM AMU/AMR, MARSEILLE, France
• ³Laboratório de Carboidratos e Radioimunoensaios- LIM18, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
• ⁴LIM 60 - Instituto do Coração-INCOR; Institute for Investigation in Immunology-iii/INCT, Heart Institute, Laboratory of Clinical Immunology and Allergy, São Paulo, Brazil
• ⁵Departamento de Genética e Biologia Evolutiva, Instituto de Biociências da Universidade de São Paulo, São Paulo, Brazil
• ⁶Parc Scientifique de Luminy, INSERM AMU/AMR, MARSELLE, France
• ⁷LIM60- Instituto do Coração-INCOR; Institute for Investigation in Immunology-iii/INCT, Heart Institute, Laboratory of Clinical Immunology and Allergy, São Paulo, Brazil

Background: 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. 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. Two IL17RA variants were significantly associated with T1D: the rs2241049G allele was linked to increased susceptibility (OR=1.42; p=0.005), whereas the rs879577A allele was related to protection (OR=0.61; p=0.021) and a reduced frequency of anti-tyrosine phosphatase (anti-IA2) autoantibody (OR= 0.52; p=0.010). Additionally, the rs5748863G allele was also associated with a lower frequency of anti-IA2 positivity (OR=0.52; p=0.010). Among IL21R variants, only rs7199138C was associated with an increased risk of T1D (OR=1.33; p=0.018). Moreover, rs2214537G and rs2285452A were linked to a reduced frequency of anti-parietal cell (OR=0.24; p<0.001) and antiendomysium (OR=0.17; p=0.025) autoantibodies, respectively. In contrast, rs2285452A and rs3093315T were related to a higher frequency of anti-thyroperoxidase (OR=2.38; p=0.028) and TSH receptor (TRAb) autoantibodies (OR=5.90; p=0.024), respectively. 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.