The goal of this proposal is to investigate the natural history of autoimmunity to pancreatic beta-cells that precedes, by years, the development of insulin-dependent diabetes mellitus (IDDM). It is hypothesized that this process is initiated by an environmental agent(s) before the age of 6 years. We postulate that beta-cell autoimmunity is relatively frequent in early childhood and that it remits in 10-25% of the cases. This study is designed to: 1) identify and prospectively follow a cohort of children aged 0-6 years, who are at a 12-40 times increased life-time risk of IDDM compared to the general population, including an estimated 166 siblings and 169 offspring of persons with IDDM in Colorado; and 200 infants with the HLA-DR3/4 phenotype and no family history of IDDM; 2) determine, in this cohort, the age-specific incidence of beta-cell autoimmunity and the sequence of autoantibodies development; 3) evaluate, in a nested case-control substudy (60 cases and 180 controls), whether a picornavirus or a cow's milk protein triggers beta- cell autoimmunity; and The participants will be recruited from an estimated 980 families with a diabetic sibling or parent and a non-diabetic child aged 0-6 years, identified mainly from the databases of the Colorado IDDM Registry. Conservatively, a 50% participation rate is assumed for those living close to Denver, though a pilot study suggested a 95% participation rate. In addition, cord blood samples from 10,000 infants born to members of The Kaiser Permanente HMO in Denver will be screened for the HLA-DR3/4 marker. A pilot study indicated that approximately 200 of the expected 560 families with HLA-DR3/4 infants (36%) will participate. The primary endpoint of this study is development of humoral autoimmunity as defined by the presence of one or more of the following autoantibodies: to cytoplasmic islet antigen (ICA), to insulin (IAA), to the GAD65 antigen and to the ICA69 islet antigen. Based on preliminary studies in Denver and Boston, 61-83 endpoints are expected. The detectable relative risk for the candidate environmental exposures is 2.3-2.7, and these exposures will be measured directly. T-cells and DNA samples will be obtained for future studies of beta-cell specific cellular autoimmunity and of its non-HLA genetic determinants. This proposed study will provide important new information urgently needed for optimal planning of primary or secondary interventions to prevent IDDM.
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| Frohnert, Brigitte I; Laimighofer, Michael; Krumsiek, Jan et al. (2018) Prediction of type 1 diabetes using a genetic risk model in the Diabetes Autoimmunity Study in the Young. Pediatr Diabetes 19:277-283 |
| Waugh, Kathleen; Snell-Bergeon, Janet; Michels, Aaron et al. (2017) Increased inflammation is associated with islet autoimmunity and type 1 diabetes in the Diabetes Autoimmunity Study in the Young (DAISY). PLoS One 12:e0174840 |
| Gu, Yong; Zhao, Zhiyuan; High, Hilary et al. (2017) Islet Autoantibody Detection by Electrochemiluminescence (ECL) Assay. J Clin Cell Immunol 8: |
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| Frohnert, Brigitte I; Ide, Lisa; Dong, Fran et al. (2017) Late-onset islet autoimmunity in childhood: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 60:998-1006 |
| Yu, Liping; Zhao, Zhiyuan; Steck, Andrea K (2017) T1D Autoantibodies: room for improvement? Curr Opin Endocrinol Diabetes Obes 24:285-291 |
| Liu, Chih-Wei; Bramer, Lisa; Webb-Robertson, Bobbie-Jo et al. (2017) Temporal profiles of plasma proteome during childhood development. J Proteomics 152:321-328 |
| Gesualdo, Patricia D; Bautista, Kimberly A; Waugh, Kathleen C et al. (2016) Feasibility of screening for T1D and celiac disease in a pediatric clinic setting. Pediatr Diabetes 17:441-8 |
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