PNNL

Abstract

Type 1 diabetes is determined by unknown environmental factors in genetically susceptible individuals. Type 1 diabetes arises from the autoimmune destruction of the insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. The design of most genetic studies of type 1 diabetes involves comparison of cases (with varying duration of disease) with controls; hence, genetic variants associated with disease ignore the factors associated with initiation of islet autoimmunity and the progression to clinical diabetes. In this study, we focused on the genetic contribution to progression of islet autoimmunity to clinical diabetes in participants from the Diabetes AutoImmunity Study in the Young (DAISY), using whole-genome sequencing. We analyzed 6.8 million variants derived from whole-genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to clinical diabetes, to determine the genetic basis of progression to diabetes. The analyses revealed four novel regions – PRPF3, NRIR, COL6A6 and TSAP1 to be associated with progression from autoimmunity to clinical diabetes (P