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.

Myopathies in Clinical Care: A Focus on Treatable Causes

“…Genetic studies have been conducted to identify risk factors and dysregulated gene expression in autoimmune myositis, aiming to understand the disease's underlying mechanisms. Genome-wide association studies (GWAS) have confirmed the human leukocyte (HLA) region as strongly associated with autoimmune myositis, with different associations observed among clinical subgroups [27]. Rare genetic variation, such as mitochondrial DNA variation and somatic mutations, have been found to contribute to disease susceptibility in specific autoimmune myositis subtypes and these mutations are thought to contribute to the pathogenesis of the disease [27].…”

“…Genome-wide association studies (GWAS) have confirmed the human leukocyte (HLA) region as strongly associated with autoimmune myositis, with different associations observed among clinical subgroups [27]. Rare genetic variation, such as mitochondrial DNA variation and somatic mutations, have been found to contribute to disease susceptibility in specific autoimmune myositis subtypes and these mutations are thought to contribute to the pathogenesis of the disease [27]. Inclusion body myositis Anti cystosolic 5' nucleotidase 1A Weakness in finger flexors and knee extensors Antisynthetase syndrome Anti-Jo 1 (Antihistidyl) Associated with fever, ILD, arthritis, Raynaud's phenomenon and mechanic's hand Anti-PL 7 (Antithreonyl) Anti-PL 12 (Antialanyl) Anti-OJ (Antiisoleucyl) Anti-EJ (Antiglycyl) Anti-KS (Antiasparaginyl) Anti-Zo (phenylalanyl) Anti-Ha (Antityrosyl).…”

“…Epigenetic modifications include histone modification, DNA methylation and microRNA activity [30]. There is also genetic overlap with autoimmune disorders [27]. In the study made by Miller et al, they evaluated 269 SNPs associated with rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes mellitus, Crohn's disease, thyroid disease, gluten-sensitive enteropathy, or multiple sclerosis.…”

Inclusion body myositis: from genetics to clinical trials

“…The reason for this difference has not yet been identified, however, hypotheses suggest that there is a gene dosage effect of genes escaping X-inactivation in 46, XX females when compared to 46, XY males. An increased rate of X chromosome aneuploidies was seen in patients with systemic lupus erythematosus and Sjögren's syndrome with a higher rate of 47, XXY (Klinefelter's syndrome) and 47, XXX [31][32][33]. The frequency of X chromosome aneuploidies was further investigated in genotyping data generated from an immunotype array.…”

Causality Assessment Between Idiopathic Inflammatory Myopathies and Lung Cancer

“…2 Idiopathic inflammatory myopathy is classified into subtypes such as dermatomyositis, polymyositis, inclusion body myositis, and immune-mediated necrotizing myositis based on clinical and histopathological features, along with the presence of myositis-specific autoantibodies. 3 The precise etiology of IIMs remains complex and not fully elucidated, with current hypotheses considering genetic predisposition, 4,5 autoimmune mechanisms, 6 and environmental factors, 7 resulting in the onset of IIMs. Treatment options for IIMs include high-dose corticosteroids along with various immunosuppressive and immunomodulatory agents.…”