Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes

Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 x 10(-8)) and three regions, 1q21.3 (MRPS21-PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 x 10(-8)) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.