Immunogenetic profiling of type 1 diabetes in Jordan: a case-control study on HLA-associated risk and protection

Objectives To comprehensively investigate the association between HLA class II alleles and haplotypes with type 1 diabetes mellitus (T1DM) susceptibility in a Jordanian population. Methods In this case-control study, 205 patients with clinically confirmed T1DM and 99 ethnically matched healthy controls were genotyped for HLA-DRB1 , DQA1 , and DQB1 loci. Autoantibodies and thyroid function were evaluated. Haplotype frequencies were compared using the BIGDAWG R package, with odds ratios (ORs), 95 % confidence intervals (CIs), and false discovery rate (FDR) correction. Results HLA-DRB1*03 : 01 (OR=4.94, p<0.001), DRB1*04 : 02 (OR=3.87, p=0.003), and DRB1*04 : 05 (case-only; p=0.002) were associated with T1DM. Strong associations were also observed for DQA1*05 : 01 (OR=6.61, p<0.001) and DQB1*02 : 01 (OR=5.70, p<0.001). Protective effects were identified for DRB1*07 : 01 , DRB1*15 : 02 , DQA1*05 : 05 , and DQB1*03 : 01 (all FDR<0.05). Among haplotypes, DR3∼DQ2 conferred the greatest risk (OR=5.40, p<0.001), while DRB1*11 : 04∼DQA1*05 : 05∼DQB1*03 : 01 was protective (OR=0.25, p=0.004). DRB1*03 : 01 was associated with GAD65 autoantibodies and celiac serology. DQA1*03 : 01 and DQA1*05 : 01 were linked to thyroid autoantibodies. No significant differences in age or HbA1c at diagnosis were observed across HLA alleles. Conclusions HLA class II variation was strongly associated with T1DM in Jordan, with DR3∼DQ2 and DR4 haplotypes driving susceptibility and DRB1*07 , DRB1*15 : 02 , and DQB1*03 : 01 conferring protection, reflecting global patterns while highlighting region-specific features. These findings support incorporating HLA genotyping into T1DM risk assessment and suggest shared genetic links with other autoimmune diseases.