BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.

Center for Microbial Pathogenesis Abigail Wexner Research Institute Nationwide Children's Hospital Columbus Ohio USA

Centre for Genetics and Genomics Versus Arthritis Centre for Musculoskeletal Research Faculty of Biology Medicine and Health University of Manchester Manchester UK

Department of Microbiology and Immunology Loyola University Chicago Maywood IL USA

Department of Neurology Ghent University Hospital Ghent Belgium

Department of Pediatrics Northwestern University Feinberg School of Medicine Chicago Illinois USA

Department of Transfusion Medicine NIH Clinical Center National Institutes of Health Bethesda MD USA

Division of Allergy Immunology and Rheumatology University at Buffalo Jacobs School of Medicine and Biomedical Sciences Buffalo NY USA

Division of Biostatistics The Ohio State University Columbus Ohio USA

Division of Informatics Imaging and Data Sciences School of Health Sciences Faculty of Biology Medicine and Health University of Manchester Manchester UK

Division of Population Health Health Services Research and Primary Care Faculty of Biology Medicine and Health University of Manchester Manchester UK

Division of Rheumatology Department of Medicine George Washington University School of Medicine and Health Sciences Washington DC USA

Division of Rheumatology Department of Medicine Solna Karolinska Institutet University Hospital Karolinska Stockholm Sweden

Division of Rheumatology Nationwide Children's Hospital and Department of Pediatrics The Ohio State University Columbus Ohio USA

Environmental Autoimmunity Group Clinical Research Branch National Institute of Environmental Health Sciences National Institutes of Health Bethesda MD USA

Faculty of Science and Engineering Manchester Metropolitan University Manchester UK

Institute of Rheumatology and Department of Rheumatology Charles University Prague Czech Republic

National Institute for Health Research Manchester Biomedical Research Centre Manchester University NHS Foundation Trust The University of Manchester Manchester UK

University of Mississippi Medical Center Jackson Mississippi USA

Veteran's Affairs Medical Center University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation Oklahoma City OK USA

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