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.

• MeSH
• alely MeSH
• běloši genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• haplotypy MeSH
• heterozygot MeSH
• HLA antigeny * genetika   MeSH
• HLA-DQ alfa řetězec genetika   MeSH
• HLA-DRB1 řetězec genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myozitida * genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• HLA antigeny * MeSH
• HLA-DQ alfa řetězec MeSH
• HLA-DQA1 antigen MeSH Prohlížeč
• HLA-DRB1 řetězec MeSH

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

• MeSH
• celogenomová asociační studie MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• myozitida * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

BACKGROUND: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. METHODS: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. FINDINGS: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup. INTERPRETATION: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

• Klíčová slova
• Autoantibody, HLA, Idiopathic inflammatory myopathy, Myositis,
• MeSH
• alely MeSH
• autoprotilátky * genetika   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• haplotypy MeSH
• HLA-DRB1 řetězec genetika   MeSH
• lidé MeSH
• myozitida * genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• autoprotilátky * MeSH
• HLA-DRB1 řetězec MeSH