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

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Abstract
Background: 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. Findings: Analysis 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=1.4×10 -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=7.0×10 -7 ). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4×10 -2 ). Interpretation: 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 and may impact target screening strategies and follow-up of young children with high T1D genetic risk. Funding: European Foundation for the Study of Diabetes, Maratona da Saúde and Fundação para a Ciência e a Tecnologia.

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