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HLA‐DR‐DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity
Author(s) -
Mikk MariLiis,
Pfeiffer Sophie,
Kiviniemi Minna,
Laine AnttiPekka,
Lempainen Johanna,
Härkönen Taina,
Toppari Jorma,
Veijola Riitta,
Knip Mikael,
Ilonen Jorma
Publication year - 2020
Publication title -
pediatric diabetes
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.678
H-Index - 75
eISSN - 1399-5448
pISSN - 1399-543X
DOI - 10.1111/pedi.13073
Subject(s) - autoantibody , haplotype , medicine , autoimmunity , type 1 diabetes , human leukocyte antigen , immunology , genotype , hla dq , allele , islet , diabetes mellitus , antigen , genetics , antibody , endocrinology , biology , gene
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.