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

Simon Rothwell; Hector Chinoy; Janine A Lamb; Frederick W Miller; Lisa G Rider; Lucy R Wedderburn; Neil J McHugh; Andrew L Mammen; Zoe E Betteridge; Sarah L Tansley; John Bowes; Jiří Vencovský; Claire T Deakin; Katalin Dankó; Limaye Vidya; Albert Selva-O'Callaghan; Lauren M Pachman; Ann M Reed; Øyvind Molberg; Olivier Benveniste; Pernille R Mathiesen; Timothy R D J Radstake; Andrea Doria; Jan de Bleecker; Annette T Lee; Michael G Hanna; Pedro M Machado; William E Ollier; Peter K Gregersen; Leonid Padyukov; Terrance P O'Hanlon; Robert G Cooper; Ingrid E Lundberg; Myositis Genetics Consortium (MYOGEN)

doi:10.1136/annrheumdis-2019-215046

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

Ann Rheum Dis. 2019 Jul;78(7):996-1002. doi: 10.1136/annrheumdis-2019-215046. Epub 2019 May 28.

Authors

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Autoantibodies / genetics*
Autoantibodies / immunology
Female
Genotype
HLA-DRB1 Chains / genetics*
HLA-DRB1 Chains / immunology
Haplotypes
Humans
Major Histocompatibility Complex / genetics
Male
Middle Aged
Myositis / genetics*
Myositis / immunology*
Polymorphism, Genetic
White People / genetics*

Substances

Autoantibodies
HLA-DRB1 Chains

Abstract

Publication types

MeSH terms

Substances

Grants and funding