Type 1 diabetes (T1D) results from an autoimmune destruction of pancreatic β cells. A significant gap in understanding the disease cause is the lack of predictive biomarkers for each of its developmental stages. Here, we conducted a blinded, two-phase case-control plasma proteomics analysis of children enrolled in the TEDDY study to identify biomarkers predictive of autoimmunity and T1D development. First, we performed untargeted proteomics analyses of 2,252 samples from 184 individuals and identified 376 regulated proteins. Complement/coagulation, inflammatory signaling and metabolic proteins were regulated even prior to autoimmunity onset. Extracellular matrix proteins and antigen presentation were differentially regulated in individuals with autoimmunity who progressed to T1D versus those who maintained normoglycemia. We then performed targeted proteomics measurements of 167 proteins in 6,426 samples from 990 individuals and validated 83 biomarkers. A machine learning analysis predicted both the development of persistent autoantibodies and T1D onset 6 months before autoimmunity initiation, with an area under the receiver operating characteristic curve of 0.871 and 0.918, respectively. Our study identified and validated biomarkers highlighting pathways affected in different stages of T1D development.
The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta‐cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen‐2 (IA‐2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high‐risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first‐appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first‐appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3–4 years of age. GADA first appeared by 2–3 years of age to reach a plateau by about 4 years. Prior to the first‐appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D.
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