Allelic variants of genes of the main histocompatibility complex in children with type 1 diabetes mellitus who became ill at preschool age

Abstract

BACKGROUND: Type 1 diabetes mellitus (DM1) is a chronic autoimmune disease characterized by damage to insulin–producing cells of the pancreas, which eventually leads to the need for insulin replacement therapy. The clinical picture of DM1 is heterogeneous: the onset of the disease at an early age is characterized by a more acute manifestation and rapid depletion of residual insulin secretion. Variations of HLA genes can probably determine the clinical features of the course of DM1. To date, age-related features of HLA genes have been established in various populations, at the same time, such data are not available in the Russian population.AIM: To study the effect of HLA genes on predisposition to DM1 in preschool age.MATERIALS AND METHODS: A single-center, one-stage study, including data from 885 children (1 year — 18 years old) with previously diagnosed DM1 who are on intensified insulin therapy. The study participants’re divided into two groups: a group with a manifestation of DM1 <7 years and a group with a manifestation of DM1 ≥7 years. The age of diagnosis of DM1, SDS body mass index, glycated hemoglobin (HbA1c) and C-peptide levels, specific islet autoantibodies glutamate decarboxylase (GADA), tyrosine phosphase (IA-2A), zinc transporter (ZnT8A), HLA genes of classes I and II (NGS genotyping by high-performance sequencing) were analyzed.RESULTS: In the group with manifestations of DM1 <7 years, lower levels of C-peptide’re detected (0 vs. 0.3 ng/ml, p<0.001), AT GAD was less often determined (48% vs. 67%, p=0.028), IA-2 (52% vs. 62%, p=0.014), ZnT8 (44% vs. 71%, p=0.002). There were no significant differences in the sex ratio, the level of HbA1c and SDS BMI. In the group with manifestations of DM1 <7 years, there was a high frequency of the most severe predisposing genotype DRB1*03-DQA1*05:01-DQB1*02:01 (DR3-DQ2)/DRB1*04-DQA1*03:01-DQB1*03:02 (DR4-DQ8) (27.5% vs 21.5%, p=0.039]) and a lower frequency of the protective haplotype DRB1*01-DQA1*01-DQB1*05:01 (19.1% vs. 24.9%, p=0.035). With respect to class I HLA genes, in the group with manifestation <7 years, there was a high frequency of predisposing haplotype A*24:02 (35.6% vs. 24.1%, p=0.002). Regardless of the age of onset and duration of the disease, the absence of residual C-peptide secretion (<0.1ng/ml) was associated with the presence of the predisposing haplotype DR4-DQ8 (65.7% vs. 60.8%, p=0.04) and B*18:01 (20.9% vs. 16.9%, p=0.026), and also with a lower frequency of tread haplotypes DRB1*15-DQA1*01:03-DQB1*06:03 or DRB1*15-DQA1*01:02-DQB1*06:02 (1.3% vs. 3.3%, p=0.047). The presence of IA-2A and ZnT8A was associated with the DR4-DQ8 haplotype (28.2% vs. 16.5%, p=0.037, and 33.3% vs. 15.4%, p=0.018, respectively). GADAs were associated with the predisposing haplotype DR3-DQ2 (55.0% vs. 34.5%, p=0.03).CONCLUSION: Predisposing and protective HLA haplotypes of class I and II associated with the manifestation of DM1 in preschool age and the reserve function of beta cells have been established in the Russian population. The relationship of the presence of islet AT with predisposing DR3/DR4 haplotypes is shown, which can determine various mechanisms of formation and course of the autoimmune process.