Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups.

Autor:	Rothwell S; Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK s.rothwell@manchester.ac.uk., Chinoy H; National Institute for Health Research Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.; Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK., Lamb JA; Centre for Epidemiology, The University of Manchester, Manchester, UK., Miller FW; Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, Bethesda, Maryland, USA., Rider LG; Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, Bethesda, Maryland, USA., Wedderburn LR; NIHR Great Ormond Street Biomedical Research Centre, University College London, London, UK.; Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, UK., McHugh NJ; Pharmacy and Pharmacology, University of Bath, Bath, UK., Mammen AL; 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.; Departments of Neurology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Betteridge ZE; Pharmacy and Pharmacology, University of Bath, Bath, UK., Tansley SL; Pharmacy and Pharmacology, University of Bath, Bath, UK.; Royal National Hospital for Rheumatic Diseases, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK., Bowes J; Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester, UK., Vencovský J; Institute of Rheumatology and Department of Rheumatology, Charles University, Prague, Czech Republic., Deakin CT; NIHR Great Ormond Street Biomedical Research Centre, University College London, London, UK.; Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, UK., Dankó K; Internal Medicine, University of Debrecen, Debrecen, Hungary., Vidya L; Rheumatology Unit, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia., Selva-O'Callaghan A; Internal Medicine Department, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain., Pachman LM; Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA., Reed AM; Pediatrics, Duke University, Durham, North Carolina, USA., Molberg Ø; Department of Rheumatology, University of Oslo, Oslo, Norway., Benveniste O; Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière University Hospital, France, France., Mathiesen PR; Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark., Radstake TRDJ; Department of Rheumatology and Clinical Immunology, Utrecht Medical Center, Utrecht, The Netherlands., Doria A; Division of Rheumatology, University of Padova, Padova, Italy., de Bleecker J; Department of Neurology, Ghent University, Ghent, Belgium., Lee AT; Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA., Hanna MG; MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, University College London Institute of Neurology, London, UK., Machado PM; Department of Rheumatology, University College London Hospital NHS Foundation Trust, London, UK.; Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK., Ollier WE; Centre for Epidemiology, The University of Manchester, Manchester, UK.; School of Healthcare Sciences, Manchester Metropolitan University, Manchester, Greater Manchester, UK., Gregersen PK; Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA., Padyukov L; Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden., O'Hanlon TP; Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, Bethesda, Maryland, USA., Cooper RG; MRC/ARUK Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, Merseyside, UK., Lundberg IE; Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2019 Jul; Vol. 78 (7), pp. 996-1002. Date of Electronic Publication: 2019 May 28.
DOI:	10.1136/annrheumdis-2019-215046
Abstrakt:	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. Competing Interests: Competing interests: JV reports grants from Ministry of Health in the Czech Republic, grants from European Community’s FP6, AutoCure LSHB CT-2006-01866, grants from European Science Foundation, during the conduct of the study. IEL reports grants from Swedish Research Council, grants from European Science Foundation, grants from Association Francaise Contre Les Myopathies (AFM), grants from Stockholm County Council, grants from The European Union Sixth Framework Programme, during the conduct of the study. (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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