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Ann Rheum Dis. 2016 Aug;75(8):1558-66. doi: 10.1136/annrheumdis-2015-208119. Epub 2015 Sep 11.

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.

Author information

1
Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK.
2
Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
3
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
4
Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Science, National Institutes of Health, Bethesda, Maryland, USA.
5
The Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA.
6
Institute of Rheumatology and Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
7
Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary.
8
Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia.
9
Department of Internal Medicine, Vall d'Hebron Hospital, Barcelona, Spain.
10
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
11
Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
12
Department of Pediatrics, Duke University, Durham, North Carolina, USA.
13
Arthritis Research UK, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
14
Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
15
Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
16
Pitié-Salpêtrière Hospital, UPMC, APHP, Paris, France.
17
Paediatric Department, Naestved Hospital, Næstved, Denmark.
18
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
19
Department of Medicine, University of Padova, Padova, Italy.
20
Department of Neurology, Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
21
Department of Rheumatology and Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
22
Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.
23
Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
24
Institute of Human Genetics, Technische Universität München, Munich, Germany Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
25
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.
26
Arthritis Research UK Centre for Adolescent Rheumatology, and Institute of Child Health, University College London, London, UK.
27
National Institute of Health Research Manchester Musculoskeletal Biomedical Research Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester, 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.

KEYWORDS:

Dermatomyositis; Gene Polymorphism; Polymyositis

PMID:
26362759
PMCID:
PMC5300750
DOI:
10.1136/annrheumdis-2015-208119
[Indexed for MEDLINE]
Free PMC Article

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