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

Onengut-Gumuscu, Suna; Paila, Umadevi; Chen, Wei-Min; Ratan, Aakrosh; Zhu, Zhennan; Steck, Andrea K.; Frohnert, Brigitte; Waugh, Kathleen; Webb-Robertson, Bobbie-Jo M.; Norris, Jill; Lange, Leslie A.; Rewers, Marian; Rich, Stephen S.

doi:10.1038/s41598-020-75690-6

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

Journal Article · Thu Nov 05 00:00:00 EST 2020 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-020-75690-6· OSTI ID:1713200

Onengut-Gumuscu, Suna ^[1]; Paila, Umadevi ^[1]; Chen, Wei-Min ^[1]; Ratan, Aakrosh ^[1]; Zhu, Zhennan ^[1]; Steck, Andrea K. ^[2]; Frohnert, Brigitte ^[2]; Waugh, Kathleen ^[2]; Webb-Robertson, Bobbie-Jo M. ^[3]; Norris, Jill ^[2]; Lange, Leslie A. ^[2]; Rewers, Marian ^[2]; Rich, Stephen S. ^[1]

Univ. of Virginia, Charlottesville, VA (United States)
Univ. of Colorado Anschutz Medical Campus, Aurora, CO (United States)
Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Univ. of Colorado Anschutz Medical Campus, Aurora, CO (United States)

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 × 10^–8) and three regions, 1q21.3 (MRPS21–PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 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.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: Leona M. and Harry B. Helmsley Charitable Trust; National Institutes of Health (NIH); USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1713200

Report Number(s):: PNNL-SA--151476

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 10; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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