Leandro Balzano-Nogueira1, Ricardo Ramirez1, Tatyana Zamkovaya1, Jordan Dailey1, Alexandria N Ardissone1, Srikar Chamala2, Joan Serrano-Quílez3, Teresa Rubio4, Michael J Haller5, Patrick Concannon2,6, Mark A Atkinson5, Desmond A Schatz5, Eric W Triplett1, Ana Conesa7,8. 1. Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA. 2. Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA. 3. Gene Expression and RNA Metabolism Laboratory, Instituto de Biomedicina de Valencia (CSIC), Jaume Roig, 11, 46010, Valencia, Spain. 4. Laboratory of Neurobiology, Prince Felipe Research Center, Valencia, Spain. 5. Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA. 6. University of Florida Genetics Institute, Gainesville, FL, USA. 7. Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA. aconesa@ufl.edu. 8. University of Florida Genetics Institute, Gainesville, FL, USA. aconesa@ufl.edu.
Abstract
BACKGROUND: The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective birth cohort designed to study type 1 diabetes (T1D) by following children with high genetic risk. An integrative multi-omics approach was used to evaluate islet autoimmunity etiology, identify disease biomarkers, and understand progression over time. RESULTS: We identify a multi-omics signature that was predictive of islet autoimmunity (IA) as early as 1 year before seroconversion. At this time, abnormalities in lipid metabolism, decreased capacity for nutrient absorption, and intracellular ROS accumulation are detected in children progressing towards IA. Additionally, extracellular matrix remodeling, inflammation, cytotoxicity, angiogenesis, and increased activity of antigen-presenting cells are observed, which may contribute to beta cell destruction. Our results indicate that altered molecular homeostasis is present in IA-developing children months before the actual detection of islet autoantibodies, which opens an interesting window of opportunity for therapeutic intervention. CONCLUSIONS: The approach employed herein for assessment of the TEDDY cohort showcases the utilization of multi-omics data for the modeling of complex, multifactorial diseases, like T1D.
BACKGROUND: The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective birth cohort designed to study type 1 diabetes (T1D) by following children with high genetic risk. An integrative multi-omics approach was used to evaluate islet autoimmunity etiology, identify disease biomarkers, and understand progression over time. RESULTS: We identify a multi-omics signature that was predictive of islet autoimmunity (IA) as early as 1 year before seroconversion. At this time, abnormalities in lipid metabolism, decreased capacity for nutrient absorption, and intracellular ROS accumulation are detected in children progressing towards IA. Additionally, extracellular matrix remodeling, inflammation, cytotoxicity, angiogenesis, and increased activity of antigen-presenting cells are observed, which may contribute to beta cell destruction. Our results indicate that altered molecular homeostasis is present in IA-developing children months before the actual detection of islet autoantibodies, which opens an interesting window of opportunity for therapeutic intervention. CONCLUSIONS: The approach employed herein for assessment of the TEDDY cohort showcases the utilization of multi-omics data for the modeling of complex, multifactorial diseases, like T1D.
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