HLA-DR genotypes influence age at disease onset in children and juveniles with type 1 diabetes mellitus

Abstract

ObjectiveTo investigate HLA-DR genotype in association with chronological age or calendar year of disease onset and the time trend of genotype frequencies from 1969 to 2009. Additionally, to examine genotype frequency in relation to B-cell-, islet cell antibodies (ICA)-, autoantibodies to insulin-, insulinoma antigen 2 (IA2)-, glutamic acid decarboxylase-antibody positivity, thyroid antibody positivity, thyroid diseases or coeliac antibody positivity. Genotype associations with gender and ethnicity are also analyzed.Subjects and methodsHLA-typed children and juveniles (n=1445) aged ≤20 years at disease onset from the German/Austrian DPV-database were examined.χ2statistics and mixed hierarchical logistic regression models were used to compare genotype frequencies and establish associations with age at disease manifestation, autoimmune antibodies/diseases, ethnicity and time trend.ResultsSubjects aged <6 years predominantly carried the genotype HLA-DR3/4 (25.2%), whereas in subjects aged >12 years the most prevalent HLA-DR genotype was X/X (18.1%). IA2 positivity was associated with HLA-DR4/X and HLA-DR3/4 positivity (P=0.011), and hypothyroidism was linked to HLA-DR4/4 (P=0.0103). More females carried the HLA-DR4/4 genotype (18.2 vs 12.7%P=0.0048) or were thyroid antibody positive (24.5 vs 14.7%P=0.0001). Larger numbers of <6 year olds were coeliac antibody positive than >12 year olds (14.8 vs 9.1%P=0.0037). No associations between migration background and B-cell-, thyroid- or coeliac-antibody positivity, and no time trend were found.ConclusionHLA-DR genotype associated with age at disease onset, ICA positivity and hypothyroidism; female gender with thyroid antibody positivity and low age of diabetes onset with coeliac antibody positivity.