Type 1 diabetes is a chronic autoimmune disease, in which insulin secreting beta cells in the pancreas are destroyed. The disease pathogenesis can be divided into an asymptomatic preclinical phase and symptomatic disease. The preclinical phase is characterised by the appearance of autoantibodies targeting pancreatic islet antigens and clinical onset of disease happens after the amount of functional beta cells becomes too low to sustain glucose homeostasis. While several genetic and environmental type 1 diabetes risk factors have been identified, the exact mechanism of the autoimmune process leading to the disease remains unknown. Additionally, strong heterogeneity in the disease pathogenesis has been observed and different possible pathways, or endotypes, to type 1 diabetes are suspected. The focus of this thesis was to investigate factors leading to heterogeneity in type 1 diabetes pathogenesis.

Several type 1 diabetes predisposing genetic polymorphisms, including the loci NRP1, INS, UBASH3A and STAT4, were found to associate with specific phases of disease pathogenesis. Moreover, other disease risk polymorphisms, like PTPN22 and INS, associated significantly with suspected type 1 diabetes endotypes defined through the first appearing islet autoantibody. The autoimmune risk variant of PTPN22 was also associated with elevated total and naïve regulatory T cell frequencies. No gene expression differences could be detected in individual genes between children positive for multiple type 1 diabetes associated autoantibodies and their healthy controls in monocytes and monocyte-depleted peripheral blood mononuclear cells. However, gene sets relating to viral responses and a type I interferon response were upregulated in monocytes of multiple autoantibody positive children, compared to healthy controls.

These data lend support to heterogeneity of type 1 diabetes with multiple possible pathways to disease onset.