Within a large international collaborative study, lead by Norbert Hübner (Max-Delbrück-Centrum für Molekulare Medizin (MDC) in Berlin-Buch, Germany) and Stuart Cook (Imperial College London, UK), European scientists have now identified a gene network modulating type 1 diabetes risk. Furthermore, the scientists identified a key receptor within this important genetic framework.
The current multidimenstional approach was based on genetic as well as gene expression data in different species and provided new insights in respect that the innate viral response pathway and immune cells called macrophages are also implicated in T1D.
Transcription factors play a major role in regulating gene expression by binding to specific target sequences close to the gene of interest. Importantly, a transcription factor often regulates not only one gene but whole gene networks. “In recent years a multiplicity of risk genes has been discovered which play an important role in the development of various diseases. Despite this, though, the molecular mechanism that influences the onset of the diseases has not yet been fully understood” explains a leader of this currently published study, Prof. Dr. Norbert Huebner. “We have identified a transcription factor which controls a gene network in which a well known Diabetes mellitus Type 1 risk gene occurs.
“Further analysis of the data”, concluded Prof. Huebner, “revealed that the IDIN (interferon regulatory factor 7 (IRF71)-driven inflammatory network ) gene essentially influences Diabetes mellitus type 1 risk via the receptor EBI2 which regulates IDIN and thus plays a role in the development of this autoimmune disease. Additionally we were able to show the involvement of macrophages in the pathogenesis as well as able to show that similar signaling pathways are involved in Diabetes mellitus type 1 and Epstein Barr virus infection.”
More broadly, the study is of interest because it successfully combines gene networks and DNA sequence variation to emphasize the fact that regulatory regions that perturb biological networks can have an important role in disease risk.
“The present study is an extraordinary example of combining different genetic approaches, involving genome wide expression data from rats and humans as well as genome wide association data resulting in new and exciting insights into disease pathogenesis” explained Prof. Dr. Heribert Schunkert, coordinator of Cardiogenics. “In addition, it is a success story based on international collaboration between working groups and consortia with very different expertise” adds Prof. Dr. Jeanette Erdmann, scientific project manager of Cardiogenics.
The Cardiogenics consortium (www.cardiogenics.eu) has played its role in this work bringing experimental monocyte and macrophage expression data and expertise from its own focus on the assessment of heart attack risk to aid understanding of another important common disease. This EU project has gathered together leading research groups from six countries (Germany, United Kingdom, France, The Netherlands, Sweden, and Italy) to build a multi-disciplinary team to meet the challenge of improving cardiovascular healthcare. In addition to clinical teams, the consortium consists of academic groups specialized in human genetics, genetic epidemiology, bioinformatics, transcriptomics, and proteomics. In addition, the consortium has been supported by the Welcome Trust Sanger Institute, Europe's premier genome centre.A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk
M. Heinig*, E. Petretto*, C. Wallace, L. Bottolo, M. Rotival, H. Lu, Y. Li, R. Sarwar, S.R. Langley, A. Bauerfeind, O. Hummel, Y.-A. Lee, S. Paskas, C. Rintisch, K. Saar, .J Cooper, R. Buchan, E.E. Gray, J.G. Cyster, Cardiogenics Consortium, J. Erdmann, C. Hengstenberg, S. Maouche, W.H. Ouwehand, C.M. Rice, N.J. Samani, H. Schunkert, A.H. Goodall, H. Schulz, H. Roider, M. Vingron, S. Blankenberg, T. Münzel, T. Zeller, S. Szymczak, A. Ziegler, L. Tiret, D.J. Smyth, M. Pravenec, T.J. Aitman, F. Cambien, D. Clayton, J.A. Todd, N. Hubner* und S.A. Cook* (*contributed equally)
Nature advance online publication 08.09.2010: http://www.nature.com/Contact
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