HLA‐DR‐DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity

Abstract

Objective: We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity. Methods: Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes (T1D) from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A); and genotyped for HLA DR/DQ alleles. In the DIPP study, autoantibodies were regularly analyzed from birth up to 15 years of age. Results: In the DIPP cohort, 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268, and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody, whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR. Conclusions: These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response.

Heterogeneity in the presentation of clinical type 1 diabetes defined by the level of risk conferred by human leukocyte antigen class II genotypes

“…This is in line with previous studies reporting that the male gender is associated with a higher incidence of T1D particularly in Caucasian populations with high disease rates 38 . Our findings are also in line with previous studies on the differences of T1D risk depending on the affected family member, as the frequency of paternal T1D has been observed to be almost two times higher than that of maternal T1D 39,40 . Furthermore, an increased frequency of affected family members in participants with higher risk HLA genotypes seen in our study has been reported earlier 32,41 …”

“…There were also differences in the frequency of various autoantibodies in the two groups studied. IAA and IA‐2A are known to be strongly associated with the HLA DR4‐DQ8 haplotype, especially when including the DRB1*04:01 allele, which is the high‐risk DRB1 haplotype, whereas GADA is associated with the weaker DR3‐DQ2 susceptibility haplotype 40 . Indeed, among our study subjects IAA, ICA, and IA‐2A were more frequent in Group 1 carrying high or moderate‐risk genotypes for T1D whereas GADA were more frequent in Group 2 with lower HLA‐conferred risk for T1D.…”

Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes

“…The associations of the DR4‐DQ8 haplotype with IAA and the DR3‐DQ2 haplotype with GADA are well known 23–26 and follow‐up studies from birth confirmed these associations especially in the case of the first emerging autoantibody 9–11 . More precisely we recently demonstrated the IAA association to be seen particularly in those carrying the DRB1*04:01 allele in the DR4‐DQ8 haplotype whereas the other common DR4 allele in this haplotype in the Northern European populations, DRB1*04:04, was actually more associated with GADA‐initiated autoimmunity 13 . The difference was clear both in the DIPP follow‐up study and in the deduced first autoantibody cohort in the largely overlapping FPDR series as analyzed here.…”

Etiology of Autoimmune Islet Disease: Timing Is Everything

“…DR-DQ heterodimers may display autoantigen epitopes to initiate the autoimmune response that leads to the appearance of a first islet autoantibody. As discussed previously, the association between HLA and T1D may be secondary to the primary association between HLA and either IAA or GADA as the first-appearing islet autoantibody (23,38,42). This view is supported by the observation that HLA was not associated with the progression from two or more islet autoantibodies to the clinical onset of T1D (4,38,43).…”

“…However, as children were recruited at birth based on T1D risk HLA types, it was possible to test if HLA DR-DQ alleles and haplotypes were associated with the type of the first-appearing islet autoantibody. Highly significant differences in the association between the first autoantibody and HLA were reported in both TEDDY (23,38) and DIPP (42). In both studies, homozygotes for DR3-DQ2 had predominantly GADA as the first autoantibody.…”