Effects of the genome on immune regulation in type 1 diabetes.

Type 1 diabetes (T1DM) is a complex disease, arising through the interaction of an incompletely defined combination of genetic susceptibility and environmental factors. It is well accepted that T1DM results from selective immune-mediated destruction of the insulin-producing ß cells in the islets of langerhans. Genetic studies of T1DM have identified several regions of susceptibility and identified major networks and pathways contributing to risk. In this study, we have taken advantages of the Immunochip fine-mapping genotyping data to address different aspects of immune regulation in relation to T1DM. First, we confirm that dense single nucleotide polymorphism (SNP) genotyping of the major histocompatibility complex/human leukocyte antigen (MHC/HLA) region capture the complex genetic contribution of this region to disease risk. Furthermore, it is shown that Immunochip genotyping can translate into a limited number of DRB1 and DQB1 amino acid residues that account for most of the HLA-risk. Second, we use the Immunochip data to look for functional significance by correlation to circulating levels of chemokines and demonstrate that genetic variation at chromosome 2, 3, and 6 correlates with circulating CCL2 and CCL4 in recent onset T1DM patients. Finally, we report that genetic variants predict autoantibody positivity in T1DM cases.