Non-HLA risk variants in a type 1 diabetes pediatric population: Clinical and autoimmune profiles
Year: 2026
Type: article
Study design: Observational Study
Abstract: The interplay between genetic and environmental factors plays a critical role in the development of type 1 diabetes (T1D). While variants in non-HLA coding regions have been identified as potential therapeutic targets, their exact contribution to the pathophysiology of disease remains unclear. The aim of the study was to characterize six non-HLA variants in pediatric patients with T1D and explore their potential association with clinical parameters and other autoimmune diseases, such as thyroiditis and celiac disease (CD). We analyzed six variants (c.1858 T > C, c.49A > G, c.919A > G, c.784 T > C, c.461 G > A, and c.-17-6 T, located in the PTPN22, CTLA4, CD226, SH2B3, FUT2 and INS genes) in a pediatric sample (age ≤ 18 years) with T1D, comparing it with a CD group and a control group. The variants were genotyped using quantitative PCR with TaqMan probes. We observed that variants in PTPN22, CD226 and INS were overrepresented in patients with T1D compared to the control and CD groups. There was a significant association between the presence of anti-glutamate decarboxylase autoantibodies (GADA) and the CTLA4 variant ( P = .005), as well as between insulinoma-associated anti-tyrosine phosphatase autoantibodies (IA2A) and the PTPN22 variant ( P < .03).The number of positive pancreatic autoantibodies was associated with the FUT2 variant ( P = .02). Additionally, age at onset was associated with CTLA4 ( P = .01) and SH2B3 ( P < .05) variants. The analyzed variants in the PTPN22, CD226 , and INS genes were overrepresented in pediatric patients with T1D, suggesting potential therapeutic targets for modulating the autoimmune process. Their associations with specific clinical and autoimmune profiles can be applied in the identification of high-risk patients and help optimize their follow-up. La interacción entre factores genéticos y ambientales es clave en el desarrollo de la diabetes tipo 1 (DM1). Aunque las variantes en la región codificante no-HLA son potenciales marcadores para terapias dirigidas, su contribución a la enfermedad es poco conocida. Nuestro objetivo fue caracterizar 6 variantes no-HLA en pacientes pediátricos con DM1, analizando su asociación con parámetros clínicos y otras patologías autoinmunes (tiroiditis y enfermedad celiaca –EC–). Se analizaron las variantes c.1858 T > C, c.49A > G, c.919A > G, c.784 T > C, c.461 G > A y c.-17-6T > A en los genes PTPN22, CTLA4, CD226, SH2B3, FUT2 e INS en una población pediátrica con DM1 (≤18a), comparándola con un grupo control y otro con EC. Las variantes se identificaron mediante PCR cuantitativa usando sondas Taqman. Observamos sobrerrepresentación de las variantes en PTPN22 , CD226 e INS en los pacientes con DM1 frente a los grupos con EC y control. Encontramos asociación entre la presencia de autoanticuerpos antiglutamato descarboxilasa (GADA) y la variante en CTLA4 (p = 0,005), y entre autoanticuerpos antitirosina fosfatasa asociados a insulinoma (IA2A) y la variante en PTPN22 (p < 0,03). El número de autoanticuerpos pancreáticos positivos mostró asociación con la variante en FUT2 (p = 0,02). La edad al debut se asoció con las variantes en CTLA4 (p = 0,01) y en SH2B3 (p < 0,05). Los pacientes pediátricos con DM1 tienen sobrerrepresentadas las variantes analizadas en los genes PTPN22 , CD226 e INS, señalando posibles dianas terapéuticas que modulen el proceso autoinmune. Su asociación con determinados perfiles clínicos y autoinmunes podría ayudar a identificar pacientes de riesgo y optimizar su seguimiento.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7119780233