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A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

2010; Nature Portfolio; Volume: 467; Issue: 7314 Linguagem: Inglês

10.1038/nature09386

1476-4687

Matthias Heinig, Enrico Petretto, Chris Wallace, Leonardo Bottolo, Maxime Rotival, Lu Han, Yoyo Li, Rizwan Sarwar, Sarah R. Langley, Anja Bauerfeind, Oliver Hummel, Young‐Ae Lee, Svetlana Paskaš, Carola Rintisch, Kathrin Saar, Jason D. Cooper, Rachel Buchan, Elizabeth Gray, Jason G. Cyster, Jeanette Erdmann, Christian Hengstenberg, Seraya Maouche, Willem H. Ouwehand, Catherine M. Rice, Mark M. Iles, Heribert Schunkert, Alison H. Goodall, Herbert Schulz, Helge G. Roider, Martin Vingron, Stefan Blankenberg, Thomas Münzel, Tanja Zeller, Silke Szymczak, Andreas Ziegler, Laurence Tiret, Deborah J. Smyth, Michal Pravenec, Timothy J. Aitman, François Cambien, David Clayton, John A. Todd, Norbert Hübner, Stuart A. Cook,

Genetic Associations and Epidemiology

Genome-wide association studies (GWAS) have highlighted a number of genes with connections to type 1 diabetes and other common diseases, but in most instances the mechanism by which DNA variation affects disease risk is far from clear. Recent advances in rat genomics now make a systems-genetics approach possible, which should help to reveal links between diseases and gene functions. Using gene expression studies across seven types of rat tissue, together with GWAS and human genetics, Heinig et al. have now identified the inflammatory network driven by interferon regulatory factor 7 (IRF7) as a contributor to type 1 diabetes risk. They also implicate the innate viral response pathway and macrophages in the aetiology of the disease. The study shows how co-expression networks across species provide functional annotation of genes, and how this can be used to reveal a signal of common genetic variation of small effect that is not detected by GWAS. Here, a combination of genetic studies of gene expression, cross-species network analysis and genome-wide association studies has been used to identify gene networks and the loci underlying their regulation in rats. The results show that an inflammatory network driven by interferon regulatory factor 7 contributes to susceptibility to type 1 diabetes, and implicate the innate viral-response pathway and macrophages in the aetiology of this disease. Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches1,2. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF73)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein–Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration4,5, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)—a macrophage-associated autoimmune disease—than randomly selected immune response genes (P = 8.85 × 10−6). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 10−10; odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.