Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies

• Published in: Annals of the rheumatic diseases Vol. 82; no. 2; pp. 235 - 245
• Main Authors: Zhou, Danlei, King, Emily H, Rothwell, Simon, Krystufkova, Olga, Notarnicola, Antonella, Coss, Samantha, Abdul-Aziz, Rabheh, Miller, Katherine E, Dang, Amanda, Yu, G Richard, Drew, Joanne, Lundström, Emeli, Pachman, Lauren M, Mamyrova, Gulnara, Curiel, Rodolfo V, De Paepe, Boel, De Bleecker, Jan L, Payton, Antony, Ollier, William, O'Hanlon, Terrance P, Targoff, Ira N, Flegel, Willy A, Sivaraman, Vidya, Oberle, Edward, Akoghlanian, Shoghik, Driest, Kyla, Spencer, Charles H, Wu, Yee Ling, Nagaraja, Haikady N, Ardoin, Stacy P, Chinoy, Hector, Rider, Lisa G, Miller, Frederick W, Lundberg, Ingrid E, Padyukov, Leonid, Vencovský, Jiří, Lamb, Janine A, Yu, Chack-Yung
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.02.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Adult; Age; Antigens; Autoantibodies; Autoantibodies - genetics; Autoimmune diseases; Blood vessels; C4 protein; Child; Complement C4; Complement C4a - genetics; Complement component C4; Complement system; Copy number; Dermatomyositis; Disease; DNA Copy Number Variations; Drb1 protein; Genes; Genetic diversity; Genetic Predisposition to Disease; Genomes; Health risk assessment; Histocompatibility antigen HLA; HLA-DR3 Antigen - genetics; HLA-DRB1 Chains - genetics; Humans; Immunodiffusion; Inflammation; Inflammatory diseases; Leukocytes; Medicin och hälsovetenskap; Muscles; Musculoskeletal diseases; Myositis; Polymyositis; Population studies; Proteins; Risk Factors; Skin; Czech Republic; Sweden; Ohio; United Kingdom > UK; Belgium; United States > US; polymyositis; autoantibodies; dermatomyositis
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/ard-2022-222935

BackgroundIdiopathic 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.MethodsWe 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.ResultsThe 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.