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

Nature advance online publication 8 September 2010 | doi:10.1038/nature09386; Received 18 December 2009; Accepted 28 July 2010; Published online 8 September 2010

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk
Matthias Heinig1,2,28, Enrico Petretto3,4,28, Chris Wallace5, Leonardo Bottolo3,4, Maxime Rotival6, Han Lu3, Yoyo Li3, Rizwan Sarwar3, Sarah R. Langley3, Anja Bauerfeind1, Oliver Hummel1, Young-Ae Lee1,7, Svetlana Paskas1, Carola Rintisch1, Kathrin Saar1, Jason Cooper5, Rachel Buchan3, Elizabeth E. Gray8, Jason G. Cyster8, Cardiogenics Consortium, Jeanette Erdmann9, Christian Hengstenberg10, Seraya Maouche6, Willem H. Ouwehand11,12, Catherine M. Rice12, Nilesh J. Samani13, Heribert Schunkert9, Alison H. Goodall13, Herbert Schulz1, Helge G. Roider2, Martin Vingron2, Stefan Blankenberg14, Thomas Münzel14, Tanja Zeller14, Silke Szymczak15, Andreas Ziegler15, Laurence Tiret6, Deborah J. Smyth5, Michal Pravenec16, Timothy J. Aitman3, Francois Cambien6, David Clayton5, John A. Todd5, Norbert Hubner1,17 & Stuart A. Cook3,18

Correspondence to: Norbert Hubner1,17 Email: nhuebner@mdc-berlin.de

Correspondence to: Stuart A. Cook3,18 Email: stuart.cook@csc.mrc.ac.uk


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 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.

Nature (advance online publication 8 September 2010); doi:10.1038/nature09386
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature09386.html



GENÉTICA
Una red de genes podría favorecer el desarrollo de la diabetes tipo 1
JANO.es y agencias · 09 Septiembre 2010 10:51

Investigadores de Reino Unido utilizan un método que proporciona nueva información sobre las causas de la enfermedad.


Investigadores del Centro de Ciencias Clínicas del Consejo de Investigación Médica de Londres, en Reino Unido, han identificado una red de genes y de regiones reguladoras que podrían contribuir al riesgo de desarrollar diabetes tipo 1. Los resultados del trabajo se publican en la revista Nature.

Los estudios de asociación amplia del genoma han desvelado una variedad de genes vinculados con la diabetes tipo 1, pero en el trabajo actual, los investigadores han utilizado un método que proporciona nueva información sobre las causas de esta enfermedad.

El análisis combina diversos métodos genéticos que implican estudios de expresión genética y datos genéticos de rata y humanos para desvelar regiones de ADN que controlan la expresión de un grupo de genes asociado a T1D, el factor 7 regulador de interferon (IRF7), que dirige la red inflamatoria. El mecanismo de respuesta viral innata y las células inmunes denominadas macrófagos también están implicadas en T1D.

El estudio también resulta de interés porque combina con éxito redes de genes y variaciones en la secuencia de ADN y subraya el hecho de que las regiones reguladoras que perturban las redes biológicas pueden tener un importante papel en el riesgo de enfermedad.


Nature (advance online publication 8 September 2010); doi:10.1038/nature09386
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature09386.html

Centro de Ciencias Clínicas del Consejo de Investigación Médica de Londres
http://www.csc.mrc.ac.uk/

Nature
http://www.nature.com/nature/index.html

Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany
Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Department of Epidemiology and Biostatistics, Faculty of Medicine, Imperial College London, Praed Street, London W2 1PG, UK
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK
INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, 91 Boulevard de l’Hôpital, Paris 75013, France
Pediatric Pneumology and Immunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, California 94143, USA
Universität zu Lübeck, Medizinische Klinik II, 23538 Lübeck, Germany
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany
Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge CB2 0PT, UK
Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1SA, UK
Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK
Medizinische Klinik und Poliklinik, Johannes-Gutenberg Universität Mainz, Universitätsmedizin, Langenbeckstrasse 1, 55131 Mainz, Germany
Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Maria-Goeppert-Straße 1, 23562 Lübeck, Germany
Institute of Physiology, Czech Academy of Sciences and Centre for Applied Genomics, Videnska 1083, 14220 Prague 4, Czech Republic
CC4, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK
Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK.
Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge CB2 2PT, UK.
INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, 91 Boulevard de l’Hôpital, Paris 75013, France.
Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Regensburg, 93053 Regensburg, Germany.
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany.
Universität zu Lübeck, Medizinische Klinik II, 23538 Lübeck, Germany.
Molecular Medicine, Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
Trium, Analysis Online GmbH, Hohenlindenerstraße 1, 81677 München, Germany.
Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1SA, Cambridge.
These authors contributed equally to this work.
A list of participants and their affiliations appears at the end of the paper.