OBJECTIVES: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. RESULTS: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. CONCLUSIONS: This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.

• Keywords
• Dermatomyositis, Gene Polymorphism, Polymyositis,
• MeSH
• Alleles MeSH
• Autoimmunity genetics   MeSH
• Genome-Wide Association Study MeSH
• Dermatomyositis genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• HLA Antigens genetics   MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Quantitative Trait Loci MeSH
• Myositis genetics   immunology   MeSH
• Polymyositis genetics   MeSH
• Risk Factors MeSH
• Case-Control Studies MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Names of Substances
• HLA Antigens MeSH
• PTPN22 protein, human MeSH Browser
• Protein Tyrosine Phosphatase, Non-Receptor Type 22 MeSH