Autor(es): Caramalho, Iris ; Matoso, Paula ; Ligeiro, Dário ; Paixão, Tiago ; Sobral, Daniel ; Fitas, Ana Laura ; Limbert, Catarina ; Demengeot, Jocelyne ; Penha-Gonçalves, Carlos
Data: 2023
Identificador Persistente: http://hdl.handle.net/10362/162725
Origem: Repositório Institucional da UNL
Assunto(s): age of onset; Early-onset Type 1 diabetes; HLA class II; T1D endotypes; Type 1 diabetes; Immunology and Allergy; Immunology; SDG 3 - Good Health and Well-being
Funding Information: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the European Foundation for the Study of Diabetes (EFSD/JDRF/Lilly Programme 2016), Maratona da Saúde and Fundação para a Ciência e a Tecnologia (CEECIND/00148/2017 to Iris Caramalho). Acknowledgments Publisher Copyright: Copyright © 2024 Caramalho, Matoso, Ligeiro, Paixão, Sobral, Fitas, Limbert, Demengeot and Penha-Gonçalves.
Introduction: 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. Methods: We conducted genetic association and regularized logistic regression analyses to evaluate genotypic, haplotypic and allelic variants in DRB1, DQA1 and DQB1 genes in children with EOT1D (diagnosed at £5 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. Results: Allelic association analysis of EOT1D and LaOT1D unrelated patients in comparison with controls, revealed that the rare DRB1*04:08 allele is a distinctive EOT1D susceptibility factor (corrected p-value=7.0x10-7). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4x10-2). In corroboration, HLA class II haplotype analysis showed that the rare DRB1*04:08-DQ8 haplotype is specifically associated with EOT1D (corrected p-value=1.4x10-5) and represents the major HLA class II genetic driver and discriminative factor in the development of early onset disease. Discussion: This study uncovered that EOT1D holds a distinctive spectrum of HLA class II susceptibility loci, which includes risk factors overlapping with LaOT1D and discriminative genetic configurations. These findings warrant replication studies in larger multicentric settings encompassing other ethnicities and may impact target screening strategies and follow-up of young children with high T1D genetic risk as well as personalized therapeutic approaches.
