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.