title: Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups.
abstract: OBJECTIVE
  The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium.
  
  
  RESULTS
  The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM.
  
  
  CONCLUSIONS
  This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.
authors.affiliation: Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Rothwell
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Cooper
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.affiliation: Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Science, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Miller
authors.affiliation: The Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.affiliation: Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Vencovsky
authors.affiliation: Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Danko
authors.affiliation: Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Vidya
authors.initials: V
authors.lastname: Limaye
authors.affiliation: Department of Internal Medicine, Vall d'Hebron Hospital, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Selva-O'Callaghan
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Machado
authors.affiliation: Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Pachman
authors.affiliation: Department of Pediatrics, Duke University, Durham, North Carolina, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Reed
authors.affiliation: Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Science, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Rider
authors.affiliation: Arthritis Research UK, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Cobb
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Platt
authors.affiliation: Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Molberg
authors.affiliation: Pitié-Salpêtrière Hospital, UPMC, APHP, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Benveniste
authors.affiliation: Paediatric Department, Naestved Hospital, Næstved, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Mathiesen
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Timothy
authors.initials: T
authors.lastname: Radstake
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Doria
authors.affiliation: Department of Neurology, Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: De Bleecker
authors.affiliation: Department of Neurology, Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
authors.forename: Boel
authors.initials: B
authors.lastname: De Paepe
authors.affiliation: Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Maurer
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
authors.forename: William E
authors.initials: WE
authors.lastname: Ollier
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Science, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: O'Hanlon
authors.affiliation: The Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Lee
authors.affiliation: Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Institute of Neurogenomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.affiliation: Arthritis Research UK Centre for Adolescent Rheumatology, and Institute of Child Health, University College London, London, UK.
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
authors.affiliation: National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK.
authors.forename: Hector
authors.initials: H
authors.lastname: Chinoy
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
authors.forename: Janine A
authors.initials: JA
authors.lastname: Lamb
mesh_terms: D000483:Alleles; D015551:Autoimmunity / Q000235:genetics; D016022:Case-Control Studies; D003882:Dermatomyositis / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D009220:Myositis / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D017285:Polymyositis / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D040641:Quantitative Trait Loci; D012307:Risk Factors
chemical_list: D006680:HLA Antigens; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: Dermatomyositis; Gene Polymorphism; Polymyositis