Low copy numbers of complement <i>C4</i> and <i>C4A</i> deficiency are risk factors for myositis, its subgroups and autoantibodies.

Abstract

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 <i>C4</i> in IIM pathology was unknown. We elucidated the gene copy number (GCN) variations of total <i>C4</i>, <i>C4A</i> and <i>C4B, long</i> and <i>short genes</i> 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. The large study populations helped establish the distribution patterns of various <i>C4</i> GCN groups. Low GCNs of <i>C4T</i> (<i>C4T</i>=2+3) and <i>C4A</i> deficiency (<i>C4A</i>=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 <i>C4T</i>, and 2.82 (2.48-3.21), p=7.0×10^-57 for <i>C4A</i> deficiency. Contingency and regression analyses showed that among patients with <i>C4A</i> deficiency, the presence of <i>HLA-DR3</i> became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had <i>HLA-DR3</i> 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. <i>C4A</i> deficiency is relevant in dermatomyositis, <i>HLA-DRB1*03</i> is important in IBM and both <i>C4A</i> deficiency and <i>HLA-DRB1*03</i> contribute interactively to risk of polymyositis.