Heterogeneity in the presentation of clinical type 1 diabetes defined by the level of risk conferred by HLA class II genotypes.

The association between human leukocyte antigen (HLA) class II genotypes and susceptibility to type 1 diabetes (T1D) is well established. This study aimed at examining whether there are differences in the presentation of T1D depending on the HLA genotype. We divided the study participants (N = 5798) in the Finnish Pediatric Diabetes Register into two groups based on the T1D risk conferred by their HLA genotype (high and moderate risk genotypes, Group 1 vs. other genotypes, Group 2). We then examined differences in clinical, metabolic and immunological characteristics. Children included in the study were 0 to 14-year-old and diagnosed between January 2003 and December 2019. Participants in Group 1 were younger at the time of diagnosis (P < 0.001) and had more frequently family members affected by T1D (P < 0.001). Diabetic ketoacidosis (DKA) was more frequent among participants in Group 2 (P = 0.014) who also had a longer duration of symptoms before diagnosis (P < 0.001) and higher HbA1c (P = 0.001) at diagnosis. The HLA genotype was not, however, directly related to the DKA frequency. The frequency of ICA (P < 0.003), IAA (P < 0.001) and IA-2A (P < 0.001) was higher in Group 1 whereas GADA were more frequent (P < 0.001) in Group 2. Group 1 had more participants with multiple autoantibodies (P = 0.027) whereas antibody negativity was more frequent in Group 2 (P = 0.003). These findings indicate disease heterogeneity in relation to both clinical disease presentation and humoral autoimmunity, in particular. This heterogeneity is, at least partly, defined by HLA class II genotypes.