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

Simon Rothwell¹, Hector Chinoy^{2

3}, Janine A Lamb⁴, Frederick W Miller⁵, Lisa G Rider⁵, Lucy R Wedderburn^{6

7}, Neil J McHugh⁸, Andrew L Mammen^{9

10}, Zoe E Betteridge⁸, Sarah L Tansley^{8

11}, John Bowes¹², Jiří Vencovský¹³, Claire T Deakin^{6

7}, Katalin Dankó¹⁴, Limaye Vidya¹⁵, Albert Selva-O'Callaghan¹⁶, Lauren M Pachman¹⁷, Ann M Reed¹⁸, Øyvind Molberg¹⁹, Olivier Benveniste²⁰, Pernille R Mathiesen²¹, Timothy R D J Radstake²², Andrea Doria²³, Jan de Bleecker²⁴, Annette T Lee²⁵, Michael G Hanna²⁶, Pedro M Machado^{27

28}, William E Ollier^{4

29}, Peter K Gregersen³⁰, Leonid Padyukov³¹, Terrance P O'Hanlon⁵, Robert G Cooper³², Ingrid E Lundberg³¹; Myositis Genetics Consortium (MYOGEN)

Affiliations

¹ Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK s.rothwell@manchester.ac.uk.
² National Institute for Health Research Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
³ Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK.
⁴ Centre for Epidemiology, The University of Manchester, Manchester, UK.
⁵ Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, Bethesda, Maryland, USA.
⁶ NIHR Great Ormond Street Biomedical Research Centre, University College London, London, UK.
⁷ Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, UK.
⁸ Pharmacy and Pharmacology, University of Bath, Bath, UK.
⁹ 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.
¹⁰ Departments of Neurology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹¹ Royal National Hospital for Rheumatic Diseases, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.
¹² Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester, UK.
¹³ Institute of Rheumatology and Department of Rheumatology, Charles University, Prague, Czech Republic.
¹⁴ Internal Medicine, University of Debrecen, Debrecen, Hungary.
¹⁵ Rheumatology Unit, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia.
¹⁶ Internal Medicine Department, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.
¹⁷ Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁸ Pediatrics, Duke University, Durham, North Carolina, USA.
¹⁹ Department of Rheumatology, University of Oslo, Oslo, Norway.
²⁰ Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière University Hospital, France, France.
²¹ Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
²² Department of Rheumatology and Clinical Immunology, Utrecht Medical Center, Utrecht, The Netherlands.
²³ Division of Rheumatology, University of Padova, Padova, Italy.
²⁴ Department of Neurology, Ghent University, Ghent, Belgium.
²⁵ Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
²⁶ MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, University College London Institute of Neurology, London, UK.
²⁷ Department of Rheumatology, University College London Hospital NHS Foundation Trust, London, UK.
²⁸ Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK.
²⁹ School of Healthcare Sciences, Manchester Metropolitan University, Manchester, Greater Manchester, UK.
³⁰ Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
³¹ Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
³² MRC/ARUK Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, Merseyside, UK.

PMID: 31138531
PMCID: PMC6585280
DOI: 10.1136/annrheumdis-2019-215046

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

Simon Rothwell et al. Ann Rheum Dis. 2019 Jul.

. 2019 Jul;78(7):996-1002.

doi: 10.1136/annrheumdis-2019-215046. Epub 2019 May 28.

Authors

Affiliations

¹ Centre for Genetics and Genomics, Arthritis Research UK, University of Manchester, Manchester, UK s.rothwell@manchester.ac.uk.
² National Institute for Health Research Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
³ Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK.
⁴ Centre for Epidemiology, The University of Manchester, Manchester, UK.
⁵ Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, Bethesda, Maryland, USA.
⁶ NIHR Great Ormond Street Biomedical Research Centre, University College London, London, UK.
⁷ Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, UK.
⁸ Pharmacy and Pharmacology, University of Bath, Bath, UK.
⁹ 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.
¹⁰ Departments of Neurology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹¹ Royal National Hospital for Rheumatic Diseases, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.
¹² Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester, UK.
¹³ Institute of Rheumatology and Department of Rheumatology, Charles University, Prague, Czech Republic.
¹⁴ Internal Medicine, University of Debrecen, Debrecen, Hungary.
¹⁵ Rheumatology Unit, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia.
¹⁶ Internal Medicine Department, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.
¹⁷ Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁸ Pediatrics, Duke University, Durham, North Carolina, USA.
¹⁹ Department of Rheumatology, University of Oslo, Oslo, Norway.
²⁰ Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière University Hospital, France, France.
²¹ Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
²² Department of Rheumatology and Clinical Immunology, Utrecht Medical Center, Utrecht, The Netherlands.
²³ Division of Rheumatology, University of Padova, Padova, Italy.
²⁴ Department of Neurology, Ghent University, Ghent, Belgium.
²⁵ Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
²⁶ MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, University College London Institute of Neurology, London, UK.
²⁷ Department of Rheumatology, University College London Hospital NHS Foundation Trust, London, UK.
²⁸ Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK.
²⁹ School of Healthcare Sciences, Manchester Metropolitan University, Manchester, Greater Manchester, UK.
³⁰ Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
³¹ Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
³² MRC/ARUK Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, Merseyside, UK.

PMID: 31138531
PMCID: PMC6585280
DOI: 10.1136/annrheumdis-2019-215046

Abstract

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.

Keywords: HLA; autoantibody; genetics; idiopathic inflammatory myopathy; myositis.

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Conflict of interest statement

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.

Comment in

New insights into myositis genetics.
Onuora S. Onuora S. Nat Rev Rheumatol. 2019 Aug;15(8):451. doi: 10.1038/s41584-019-0258-y. Nat Rev Rheumatol. 2019. PMID: 31213705 No abstract available.

References

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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