title: A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes.
abstract: Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and antiviral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β-inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (n = 25). Using this predefined set of 225 IFN signature genes, we investigated the expression of the signature in cohorts of healthy controls (n = 87), patients with T1D (n = 64), and a large longitudinal birth cohort of children genetically predisposed to T1D (n = 109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically predisposed children before the development of autoantibodies (P = 0.0012) but not in patients with established T1D. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P = 0.0064), and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14(+) monocytes. DNA variation in IFN-inducible genes altered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which increased expression is a known risk factor for disease. These findings identify transient increased expression of type I IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Ferreira
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Richard M R
authors.initials: RM
authors.lastname: Coulson
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Marcin L
authors.initials: ML
authors.lastname: Pekalski
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Burren
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Cutler
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.The Australian E-Health Research Centre, Royal Brisbane and Women's Hospital, Queensland, AustraliaThe Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventative Health Flagship, Victoria, AustraliaCSIRO Mathematics and Information Sciences, Macquarie University, New South Wales, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Doecke
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Shaun
authors.initials: S
authors.lastname: Flint
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Eoin F
authors.initials: EF
authors.lastname: McKinney
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lyons
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Achenbach
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyerlein
authors.affiliation: Department of Paediatrics, School of Clinical Medicine, University of Cambridge, Cambridge, U.K.
authors.forename: David B
authors.initials: DB
authors.lastname: Dunger
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: David G
authors.initials: DG
authors.lastname: Clayton
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K. john.todd@cimr.cam.ac.uk chris.wallace@cimr.cam.ac.uk anette-g.ziegler@helmholtz-muenchen.de.
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.affiliation: CRTD-DFG Research Center for Regenerative Therapies Dresden and Paul Langerhans Institute Dresden, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.affiliation: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K. john.todd@cimr.cam.ac.uk chris.wallace@cimr.cam.ac.uk anette-g.ziegler@helmholtz-muenchen.de.
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany john.todd@cimr.cam.ac.uk chris.wallace@cimr.cam.ac.uk anette-g.ziegler@helmholtz-muenchen.de.
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
mesh_terms: D000293:Adolescent; D000328:Adult; D015551:Autoimmunity / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012306:Risk; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D007370:Interferon Type I