Genetic risk markers of type 1 diabetes within the HLA complex in children of the Volga region

   Background. Type 1 diabetes mellitus (T1DM) is characterized by pronounced genetic heterogeneity, with genes of the HLA complex playing a key role in disease susceptibility. The distribution and contribution of HLA alleles and haplotypes vary substantially between populations, highlighting the need to study population-specific features of genetic predisposition in different cohorts.

   The aim: to investigate the spectrum and frequency of HLA genes and haplotypes associated with the risk of T1DM in the Volga region.

   Material and methods. A multicenter comparative study included 507 children: 310 patients with newly diagnosed T1DM and 197 healthy siblings from three regions of the Volga area. HLA typing of loci HLA-A, -B, -C, -DR, -DQ, and -DP was performed using allele-specific PCR followed by sequencing.

   Results. Patients with T1DM demonstrated significant differences in the distribution of HLA class II haplotypes compared with healthy siblings. The DR3–DQ2 and DR4–DQ8 haplotypes were significantly associated with increased disease risk, whereas DRB1*15:01–DQA1*01:02–DQB1*06:02 and DRB1*07:01–DQA1*02:01–DQB1*03:03 showed a strong protective effect. For the DPB1 locus, opposite associations were observed: DPB1*01:01 was associated with increased T1DM risk, while DPB1*04:02 was associated with reduced risk. Interaction analysis indicated a predominantly additive effect of DPB1 and DR–DQ haplotypes, without evidence of epistatic interactions. Among HLA class I loci, B*08:01 and B*39:01 were associated with increased T1DM risk, whereas B*57:01 demonstrated a protective effect. Interactions between HLA class I and class II loci were generally additive, and some associations were partially explained by linkage disequilibrium within the HLA
region.

   Conclusion. The leading role of HLA class II haplotypes (DR3–DQ2 and DR4–DQ8) in genetic susceptibility to type 1 diabetes was confirmed. The haplotypes DRB1*15:01–DQA1*01:02–DQB1*06:02 and DRB1*07:01–DQA1*02:01–DQB1*03:03 were associated with reduced disease risk. HLA class I loci and DPB1 provide an additional, predominantly additive contribution to T1DM risk, with DPB1*01:01 conferring increased risk and DPB1*04:02 and B*57:01 showing protective effects.

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