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

BackgroundEarly-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. MethodsWe 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. FindingsAnalysis 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=1.4x10-5) 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=7.0x10-7). 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). InterpretationThis 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 and may impact target screening strategies and follow-up of young children with high T1D genetic risk. FundingEuropean Foundation for the Study of Diabetes, Maratona da Saude and Fundacao para a Ciencia e a Tecnologia.