Effects of age at seroconversion and HLA genotype on progression to diabetes in children with either IAA or GADA as the first autoantibody

Background

T1D natural history follow-up studies starting from birth have shown that usually either IAA or GADA is the first appearing islet autoantibody. Children different for these two forms differ also in autoimmunity process-associated genetic markers and distribution of seroconversion age, suggesting differences in pathogenesis of the disease. Here we compared the effects of age at seroconversion and HLA-DR/DQ genotype on the progression to clinical disease in children with either IAA or GADA as the first autoantibody in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study.

Methods

Children with increased HLA-DR/DQ-associated genetic risk were followed regularly from birth for seroconversion to IAA, GADA and IA-2A. Survival rates were assessed by log-rank test.

Results

Out of 15,253 recruited children 998 developed at least one persistent islet autoantibody. IAA was the single first autoantibody in 341 (34.2%) and GADA in 352 (35.3%) cases. Three-hundred eighty-eight of those with persistent autoantibodies progressed to clinical diabetes. Young age was associated with a rapid progress to diabetes in children with IAA as their first autoantibody (p=0.000001) but not in children with GADA as the first autoantibody (p=0.613) when age groups at seroconversion (10) were compared. HLA–DR/DQ risk level affected progression to clinical disease in both groups (p=0.00001 for IAA and p=0.013 for GADA). There was only a marginal correlation between HLA-DR/DQ risk level and age at seroconversion in the group with IAA as the first autoantibody (Spearman´s rho=-0.12, p=0.033).

Conclusions

These findings emphasize the heterogeneity of the autoimmune process revealed by the specificity of the first autoantibody and demonstrate the value of this information in prediction of the disease.