OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10-5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10-53 and HLA-DRB1*03:01, p=3.25×10-9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10-26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10-11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10-13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10-6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10-64) and position 9 of HLA-B (p=7.03×10-11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.

Ann and Robert H Lurie Children's Hospital of Chicago Northwestern University Feinberg School of Medicine Chicago Illinois USA

Arthritis Research UK Centre for Adolescent Rheumatology University College London London UK

Arthritis Research UK Centre for Genetics and Genomics The University of Manchester Manchester UK

Center for Genomics and Human Genetics The Feinstein Institute for Medical Research Manhasset New York USA

Centre for Epidemiology The University of Manchester Manchester UK

Centre for Genetics and Genomics Arthritis Research UK University of Manchester Manchester UK

Department of Internal Medicine and Clinical Immunology Pitié Salpêtrière University Hospital France France

Department of Neurology Ghent University Ghent Belgium

Department of Paediatrics and Adolescent Medicine Rigshospitalet Copenhagen Denmark

Department of Rheumatology and Clinical Immunology Utrecht Medical Center Utrecht The Netherlands

Department of Rheumatology Northwick Park Hospital London North West University Healthcare NHS Trust London UK

Department of Rheumatology University College London Hospital NHS Foundation Trust London UK

Department of Rheumatology University of Oslo Oslo Norway

Departments of Neurology and Medicine Johns Hopkins University School of Medicine Baltimore Maryland USA

Division of Rheumatology Department of Medicine Karolinska University Hospital Stockholm Sweden

Division of Rheumatology University of Padova Padova Italy

Environmental Autoimmunity Group National Institute of Environmental Health Sciences Bethesda Maryland USA

Institute of Rheumatology and Department of Rheumatology Charles University Prague Czech Republic

Internal Medicine Department Vall d'Hebron General Hospital Universitat Autonoma de Barcelona Barcelona Spain

Internal Medicine University of Debrecen Debrecen Hungary

Manchester Academic Health Science Centre Salford Royal NHS Foundation Trust Salford UK

MRC ARUK Centre for Integrated Research into Musculoskeletal Ageing University of Liverpool Liverpool Merseyside UK

MRC Centre for Neuromuscular Diseases Department of Neuromuscular Diseases University College London Institute of Neurology London UK

Muscle Disease Unit Laboratory of Muscle Stem Cells and Gene Regulation National Institute of Musculoskeletal and Skin Diseases National Institutes of Health Bethesda Maryland USA

National Institute for Health Research Manchester Biomedical Research Centre Central Manchester University Hospitals NHS Foundation Trust Manchester UK

NIHR Great Ormond Street Biomedical Research Centre University College London London UK

Pediatrics Duke University Durham North Carolina USA

Pharmacy and Pharmacology University of Bath Bath UK

Rheumatology Unit Royal Adelaide Hospital University of Adelaide Adelaide South Australia Australia

Robert S Boas Center for Genomics and Human Genetics The Feinstein Institute for Medical Research Manhasset New York USA

Royal National Hospital for Rheumatic Diseases Royal United Hospitals Bath NHS Foundation Trust Bath UK

School of Healthcare Sciences Manchester Metropolitan University Manchester Greater Manchester UK

Nat Rev Rheumatol. 2019 Aug;15(8):451. doi: 10.1038/s41584-019-0258-y. PubMed

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Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies