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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
  1. Simon Rothwell1,
  2. Robert G Cooper2,
  3. Ingrid E Lundberg3,
  4. Frederick W Miller4,
  5. Peter K Gregersen5,
  6. John Bowes1,
  7. Jiri Vencovsky6,
  8. Katalin Danko7,
  9. Vidya Limaye8,
  10. Albert Selva-O'Callaghan9,
  11. Michael G Hanna10,
  12. Pedro M Machado10,
  13. Lauren M Pachman11,
  14. Ann M Reed12,
  15. Lisa G Rider4,
  16. Joanna Cobb13,
  17. Hazel Platt14,
  18. Øyvind Molberg15,
  19. Olivier Benveniste16,
  20. Pernille Mathiesen17,
  21. Timothy Radstake18,
  22. Andrea Doria19,
  23. Jan De Bleecker20,
  24. Boel De Paepe20,
  25. Britta Maurer21,
  26. William E Ollier14,
  27. Leonid Padyukov3,
  28. Terrance P O'Hanlon4,
  29. Annette Lee5,
  30. Christopher I Amos22,
  31. Christian Gieger23,
  32. Thomas Meitinger24,25,
  33. Juliane Winkelmann26,27,
  34. Lucy R Wedderburn28,
  35. Hector Chinoy29,
  36. Janine A Lamb14
  37. the Myositis Genetics Consortium
    1. 1Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK
    2. 2Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
    3. 3Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
    4. 4Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Science, National Institutes of Health, Bethesda, Maryland, USA
    5. 5The Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA
    6. 6Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
    7. 7Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary
    8. 8Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia
    9. 9Department of Internal Medicine, Vall d'Hebron Hospital, Barcelona, Spain
    10. 10MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK
    11. 11Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
    12. 12Department of Pediatrics, Duke University, Durham, North Carolina, USA
    13. 13Arthritis Research UK, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
    14. 14Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK
    15. 15Department of Rheumatology, Oslo University Hospital, Oslo, Norway
    16. 16Pitié-Salpêtrière Hospital, UPMC, APHP, Paris, France
    17. 17Paediatric Department, Naestved Hospital, Næstved, Denmark
    18. 18Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
    19. 19Department of Medicine, University of Padova, Padova, Italy
    20. 20Department of Neurology, Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium
    21. 21Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland
    22. 22Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA
    23. 23Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany
    24. 24Institute of Human Genetics, Technische Universität München, Munich, Germany
    25. 25Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
    26. 26Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    27. 27Institute of Neurogenomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
    28. 28Arthritis Research UK Centre for Adolescent Rheumatology, and Institute of Child Health, University College London, London, UK
    29. 29National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK
    1. Correspondence to Simon Rothwell, Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester M13 9PT, UK; s.rothwell{at}manchester.ac.uk

    Abstract

    Objectives 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.

    • Dermatomyositis
    • Gene Polymorphism
    • Polymyositis

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