Expression-Based Genome-Wide Association Study Links Osteopontin and Interleukin 1 Receptor Antagonist With Newly Diagnosed Type 1 Diabetes in Children

Background: Islet autoantibodies (IAbs) are currently most reliable indicators of islet autoimmunity. However, IAbs do not fully meet the need for the prediction and intervention of type 1 diabetes (T1D). We assumed that secreted proteins associated with T1D are great sources for serum biomarkers. Methods: In an attempt to identify additional biomarkers, we performed an expression-based genome-wide association study (eGWAS) using microarray data from 169 arrays of the pancreatic islets of T1D rodents (78 T1D cases and 91 controls). We ranked all 16,099 protein-coding genes by the likelihood of differential expression in the pancreatic islets. Our top 20 secreted proteins were screened using the serum samples from newly diagnosed children with diabetes. First, we screened 20 selected candidates with 170 sera including 100 T1D, and 50 type 2 diabetes (T2D) and 20 age matched healthy children. With 6 proteins showing significance, we further did validation study using the second independent set of 400 samples from newly diagnosed children with diabetes and age matched controls including 200 T1D, 100 T2D, and 100 age-matched controls. Findings: We identified 2 serum proteins were significantly changed in T1D vs both control and T2D and 5 serum proteins were significantly changed in both T1D and T2D vs control. Serum Osteopontin (OPN) levels were uniquely higher in T1D (p<0.0001) with no difference between T2D and healthy control subjects. Serum Interleukin 1 receptor antagonist (IL-1RA) levels were lower in T1D compared with both T2D (p<0.001) and healthy subjects (p<0.0001).   Interpretation: Our results suggest that OPN and IL1RA could be the candidates of useful biomarkers for T1D in children. Funding Information: Juvenile Diabetes Research Foundation (JDRF) grant (2-SRA-2019-695-S-B), Diabetes Research Center (DRC) grant P30 DK116073. Declaration of Interests: No potential conflicts of interest relevant to this article were reported. The authors declare no conflict of interest associated with this manuscript. Ethics Approval Statement: Signed written informed consents were obtained from participants and the studies were approved by the Institutional Review Board of the University of Colorado.