The Genetics of Autoimmune Myositis

Abstract

The idiopathic inflammatory myopathies (IIM) are rare, heterogeneous systemic autoimmune disorders, characterized by inflammation of skeletal muscle and multi-organ involvement. Studies to identify genetic risk factors and dysregulated gene expression in IIM aim to increase our understanding of disease pathogenesis. Genome-wide association studies have confirmed the HLA region as the most strongly associated region in IIM, with different associations between clinically-defined subgroups. Associated genes are involved in both the innate and adaptive immune response, while identification of variants reported in other autoimmune disorders suggests shared biological pathways. Targeted imputation analysis has identified key associated amino acid residues within HLA molecules that may influence antigen recognition. These amino acids increase risk for specific clinical phenotypes and autoantibody subgroups, and suggest that serology-defined subgroups may be more homogeneous. Recent data support the contribution of rare genetic variation to disease susceptibility in IIM, including mitochondrial DNA variation in sporadic inclusion body myositis and somatic mutations and loss of heterozygosity in cancer-associated myositis. Gene expression studies in skeletal muscle, blood and skin from individuals with IIM has confirmed the role of interferon signalling and other dysregulated pathways, and identified cell-type specific signatures. These dysregulated genes differentiate IIM subgroups and identify potential biomarkers. Here, we review recent genetic studies in IIM, and how these inform our understanding of disease pathogenesis and provide mechanistic insights into biological pathways.

Keywords: gene expression; genetic risk factors; genetics; human leukocyte antigen; idiopathic inflammatory myopathies; myositis; pathogenesis.

Figure 1

Genetic overlap between idiopathic inflammatory myopathies and other autoimmune diseases. IIM associated loci meeting genome-wide significance (p<5x10^-8) for IIM as a whole, or for different clinical subgroups are indicated by the reported gene/s, and ordered by chromosomal location (x axis). Shaded squares show loci associated with IIM, and other autoimmune traits (y axis) reported in the GWAS catalogue v1.0.2 (www.ebi.ac.uk/gwas/home; Experimental Factor Ontology “Immune system disorder”). AAV, Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis; AITD, autoimmune thyroid disease; AS, ankylosing spondylitis; ASS, anti-synthetase syndrome; BS, Behcet’s syndrome; CADM, clinically amyopathic dermatomyositis; CD, celiac disease; DM, dermatomyositis; IIM, idiopathic inflammatory myopathies; JDM, juvenile dermatomyositis; JIA, juvenile idiopathic arthritis; MS, multiple sclerosis; PM, polymyositis; RA, rheumatoid arthritis; sIBM, sporadic inclusion body myositis; SLE, systemic lupus erythematosus; SS, Sjogren’s syndrome; SSc, systemic sclerosis; UC, ulcerative colitis.