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

Official URL:https://doi.org/10.1038/nature09386
PubMed:View item in PubMed
Creators Name:Heinig, M. and Petretto, E. and Wallace, C. and Bottolo, L. and Rotival, M. and Lu, H. and Li, Y. and Sarwar, R. and Langley, S.R. and Bauerfeind, A. and Hummel, O. and Lee, Y.A. and Paskas, S. and Rintisch, C. and Saar, K. and Cooper, J. and Buchan, R. and Gray, E.E. and Cyster, J.G. and Braund, P. and Gracey, J. and Krishnan, U. and Moore, J.S. and Nelson, C.P. and Pollard, H. and Attwood, T. and Crisp-Hihn, A. and Foad, N. and Jolley, J. and Lloyd-Jones, H. and Muir, D. and Murray, E. and O'Leary, K. and Rankin, A. and Sambrook, J. and Godfroy, T. and Brocheton, J. and Proust, C. and Schmitz, G. and Heimerl, S. and Lugauer, I. and Belz, S. and Gulde, S. and Linsel-Nitschke, P. and Sager, H. and Schroeder, L. and Lundmark, P. and Syvannen, A.C. and Neudert, J. and Scholz, M. and Deloukas, P. and Gray, E. and Gwilliams, R. and Niblett, D. and Erdmann, J. and Hengstenberg, C. and Maouche, S. and Ouwehand, W.H. and Rice, C.M. and Samani, N.J. and Schunkert, H. and Goodall, A.H. and Schulz, H. and Roider, H.G. and Vingron, M. and Blankenberg, S. and Muenzel, T. and Zeller, T. and Szymczak, S. and Ziegler, A. and Tiret, L. and Smyth, D.J. and Pravenec, M. and Aitman, T.J. and Cambien, F. and Clayton, D. and Todd, J.A. and Huebner, N. and Cook, S.A.
Journal Title:Nature
Journal Abbreviation:Nature
Page Range:460-464
Date:23 September 2010
Keywords:Base Sequence, Human, Pair 13 Chromosomes, Mammalian Chromosomes, Type 1 Diabetes Mellitus, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Innate Immunity, Inflammation, Interferon Regulatory Factor-7, Macrophages, Organ Specificity, Single Nucleotide Polymorphism, Quantitative Trait Loci, G-Protein-Coupled Receptors, Viruses, Animals, Rats
Abstract: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 approaches. 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 (IRF7)-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 migration, 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.
Publisher:Nature Publishing Group (U.K.)
Item Type:Article

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