107-OR: Novel Genetic Risk Factors Influence Islet Autoimmunity Progression

Background: Type 1 diabetes (T1D) is determined by unknown environmental factors in genetically susceptible individuals. The design of most genome wide association studies of T1D involves comparison of cases (with varying duration of disease) with controls; hence, the genetic variants associated with T1D reflect current disease, ignoring variants that play a key role in the initiation of islet autoimmunity and the progression of subclinical disease. In this study, we focus on the genetic contribution to progression of islet autoimmunity using whole-genome sequencing in a collection of participants of the Diabetes AutoImmunity Study in the Young (DAISY). Methods: A total of 160 persistent islet autoantibody positive DAISY subjects were sequenced, including 87 subjects who progressed to T1D and 73 “non-progressors” over a mean of 11 years since seroconversion. Following whole genome sequence alignment, single nucleotide polymorphisms (SNPs) and small insertion/deletions (indels) were identified (∼6.8 million variants), and statistical analyses performed. Results: Genes with multiple SNPs associated with progression to T1D in subjects with islet autoimmunity (P < 8.5x10-8) did not overlap with known T1D risk loci; instead, four novel regions were identified - 1q21.3 (MRPS21-PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), and 20p12.1 (TASP1). Functional mapping of the associated SNPs within these risk loci indicates pathways critical for response to viral infections and response to interferon signaling contribute to progression to T1D once islet autoimmunity is initiated. Discussion: This study presents evidence that different genetic pathways may contribute to progression of islet autoimmunity from those identified once disease is established and support the need for follow-up studies to understand genetic risk factors that modulate progression of subclinical disease. Disclosure S. Onengut-Gumuscu: None. U. Paila: None. W. Chen: None. A. Ratan: None. Z. Zhu: None. A. Steck: None. B.I. Frohnert: None. K. Waugh: None. B. Webb-Robertson: None. J.M. Norris: None. L. Lange: None. M. Rewers: None. S.S. Rich: None.