1. ¹Steno Diabetes Center, Gentofte, Denmark
2. ²Institute for Clinical Science, University of Lund, Lund, Sweden
3. ³Biosystems Department, Risø National Laboratory, Technical University of Denmark, Roskilde, Denmark
4. ⁴Neurotech A/S, Copenhagen, Denmark
5. ⁵Department of Medical Biochemistry and Genetics, University of Copenhagen, Copenhagen, Denmark
6. ⁶Molecular Diagnostic Laboratory, Aarhus University Hospital, Skejby, Aarhus, Denmark
7. ⁷Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland

Correspondence: Professor F Pociot, Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. E-mail: fpoc@steno.dk

Received 13 November 2006; Revised 21 January 2007; Accepted 22 January 2007; Published online 1 March 2007.

Abstract

We recently finemapped a type 1 diabetes (T1D)-linked region on chromosome 21, indicating that one or more T1D-linked genes exist in this region with 33 annotated genes. In the current study, we have taken a novel approach using transcriptional profiling in predicting and prioritizing the most likely candidate genes influencing beta-cell function in this region. Two array-based approaches were used, a rat insulinoma cell line (INS-1) overexpressing pancreatic duodenum homeobox 1 (pdx-1) and treated with interleukin 1 (IL-1) as well as human pancreatic islets stimulated with a mixture of cytokines. Several candidate genes with likely functional significance in T1D were identified. Genes showing differential expression in the two approaches were highly similar, supporting the role of these specific gene products in cytokine-induced beta-cell damage. These were genes involved in cytokine signaling, oxidative phosphorylation, defense responses and apoptosis. The analyses, furthermore, revealed several transcription factor binding sites shared by the differentially expressed genes and by genes demonstrating highly similar expression profiles with these genes. Comparable findings in the rat beta-cell line and human islets support the validity of the methods used and support this as a valuable approach for gene mapping and identification of genes with potential functional significance in T1D, within a region of linkage.