OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are rare autoimmune disorders. Genetic association studies have highlighted the role of human leukocyte antigen (HLA) polymorphisms in IIM. We aimed to characterise the nonadditive effects (dominance and interaction) of HLA alleles on IIM risk. METHODS: This study included a total of 3206 IIM cases and 11,697 controls of European ancestry. HLA alleles were imputed using a multiancestry HLA reference panel. Logistic regressions were conducted to estimate the nonadditive effects of HLA alleles. Clinical subgroup analysis, calculation of phenotypic variance explained, and stepwise conditional analyses were conducted to further characterise these effects. RESULTS: We identified significant nonadditive effects in 5 HLA genes, particularly in the core alleles of ancestral haplotype 8.1 (8.1 AH), including HLA-B*08:01 (P = 3.93 × 10-13), HLA-C*07:01 (P = 3.14 × 10-8), HLA-DQA1*05:01 (P = 3.03 × 10-9), HLA-DQB1*02:01 (P = 3.53 × 10-23), and HLA-DRB1*03:01 (P = 8.47 × 10-21). Notable risk difference between heterozygotes and homozygotes was observed in IIM, such as HLA-DRB1*03:01 (homozygote odds ratio [OR], 2.17; heterozygote OR, 3.13). In the interaction model, HLA-DQA1 and HLA-DRB1 showed specific significant allelic interactions. The nonadditive effect model explained a larger proportion of phenotypic variance than the model with additive effects alone. Conditional analysis indicated the independent nonadditive effect of HLA-DRB1*03:01 in 8.1 AH and amino acid residue Arg-74 in HLA-DRB1. CONCLUSIONS: This study identified significant nonadditive effects within the HLA region of IIM. A genetic risk model including nonadditive effects could provide more accurate individual risk estimates. These findings highlight a complex role of HLA heterozygosity in the development of IIM and support further research into HLA nonadditive effects with clinical relevance.

Centre for Musculoskeletal Research Faculty of Biology Medicine and Health The University of Manchester Manchester UK; NIHR Manchester Biomedical Research Centre Manchester University NHS Foundation Trust Manchester Academic Health Science Centre Manchester UK

Centre for Musculoskeletal Research Faculty of Biology Medicine and Health The University of Manchester Manchester UK; NIHR Manchester Biomedical Research Centre Manchester University NHS Foundation Trust Manchester Academic Health Science Centre Manchester UK; Department of Rheumatology Salford Royal Hospital Northern Care Alliance NHS Foundation Trust Manchester Academic Health Science Centre Salford UK

Epidemiology and Public Health Group School of Health Sciences The University of Manchester Manchester UK

Institute for Clinical and Translational Research Baylor College of Medicine Houston TX USA

Institute for Clinical and Translational Research Baylor College of Medicine Houston TX USA; Epidemiology and Population Sciences Department of Medicine Baylor College of Medicine Houston TX USA; Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine Houston TX USA

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