Journal
JOURNAL OF AUTOIMMUNITY
Volume 35, Issue 1, Pages 70-76Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2010.03.001
Keywords
Type 1 diabetes; Prediabetes; Autoantibodies; Longitudinal data; Differential gene expression; Molecular networks; Pathway analysis
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Funding
- Juvenile Diabetes Research Foundation (JDRF)
- Academy of Finland
- Turku University
- Finnish Funding Agency for Technology and Innovation (Tekes)
- Sigrid Juselius Foundation
- DIPP
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Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing pancreatic p cells in the islets of Langerhans. Although defects in various T cell subsets have been linked to the disease pathogenesis, mechanisms initiating or enhancing the autoimmunity in prediabetes remain poorly understood. To unravel genes and molecular pathways affected by the diabetes-associated autoimmunity, we investigated transcriptomic profiles of prospective whole-blood samples from children who have developed T1D-associated autoantibodies and eventually clinical T1D. Gene-level investigation of the data showed systematic differential expression of 520 probesets. A network-based analysis revealed then a highly significant down-regulated network of genes involved in antigen presentation as well as T-cell receptor and insulin signaling. Finally, detection of dynamic changes in the affected pathways at the early or late phases of autoimmunity showed down-regulation of several novel T1D-associated pathways as well as known key components of immune response. The longitudinal genome-wide data generated in the present study allows the detection of dynamic changes relevant to the disease that may be completely missed in conventional cross-sectional studies or in genome-wide association studies. Taken together, our analysis showed systemic high-level repression of immune response pathways associated with T1D autoimmunity. (C) 2010 Elsevier Ltd. All rights reserved.
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