The DR-DQ HLA haplotypes dominant-recessive interplay leads to the heterogeneity of antibody immune response in T1D

Abstract Type 1 diabetes mellitus (T1D) is an autoimmune disorder defined by the presence of islet-specific autoantibodies (AAb). Growing evidence indicates substantial heterogeneity in T1D pathogenesis, reflected in divergent AAb profiles across patient subgroups. We integrated ELISA-based measurements of four major islet autoantibodies-insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 (IA-2A), and zinc transporter 8 (ZnT8A)-with whole-genome sequencing (WGS) data from 917 individuals diagnosed with T1D or latent autoimmune diabetes in adults (LADA). Analyses were stratified by class II human leukocyte antigen (HLA) haplotypes, age at disease onset (0-55 years old), sex, and disease duration (0-51 years). To investigate seroconversion dynamics during the preclinical phase, we additionally included 72 preclinical participants. HLA haplotype emerged as the primary determinant of AAb specificity, while dominant-recessive interactions between alleles in the heterozygous state have been revealed. In addition to confirming the previously described associations between IA-2A and ZnT8A with DR4-DQ8 and GADA with DR3-DQ2, an increase in ZnT8A levels was detected for heterozygotes of the DR1-DQ5 haplotype. Moreover, even within identical HLA backgrounds, sex, age at onset, and disease duration significantly modulated the autoantibody repertoire. These findings demonstrate that HLA haplotype is a major driver of T1D heterogeneity, while non-HLA factors may modify its effects. The observed immunological heterogeneity underscores the need for multidimensional stratification in T1D research and highlights opportunities for HLA-informed prediction and monitoring during the preclinical window.