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Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

Genes & Immunity volume 16, pages 470–480 (2015)Cite this article

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Abstract

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10−8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

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Acknowledgements

This study was supported in part by: the Intramural Program of the NIH, National Institute of Environmental Health Sciences (NIEHS Z01ES101074); European Community’s FP6, AutoCure LSHB CT-2006-018661; Myositis UK; Arthritis Research UK (18474 and 20164); The Cure JM Foundation; the European Science Foundation in the framework of the Research Networking Programme European Myositis Network (EuMyoNet); Association Francaise Contre Les Myopathies (AFM), the National Institute for Health Research Biomedical Research Centre at ICH/GOSH; the National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit; the Wellcome Trust; Action Medical UK; Great Ormond Street Children’s Charity; the National Institute for Health Research Translational Research Collaboration on rare diseases; and the Swedish Research Council. The Czech cohort was partially supported by the Ministry of Health, Czech Republic (No. 00023728).

We are indebted to Dr Javier Martin (Instituto de Parasitología y Biomedicina, Granada, Spain) for supplying Spanish control data, Dr Peter Novota (Institute of Rheumatology, Prague, Czech Republic) for supplying Czech controls and Dr Lars Alfredsson (Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden) for Swedish control data. We thank Dr Younghun Han (Dartmouth College) for statistical support, Miss Hazel Platt and Mrs Fiona Marriage (Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK) and Drs Maryam Dastmalchi and Eva Jemseby (Karolinska Institutet, Stockholm, Sweden) for technical support, Mr Paul New (Salford Royal Foundation Trust, Salford, UK) for ethical and technical support, Sue Edelstein (Image Associates, Inc., Durham, NC) for graphics support and Lisa Maroski for assistance in manuscript preparation.

We thank Dr Elaine Remmers (National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD) and Dr Douglas Bell (National Institute of Environmental Health Sciences, Research Triangle Park, NC) of the National Institutes of Health for their critical review of the manuscript.

We thank the other study investigators of the Myositis Genetics Consortium: Drs Christopher Denton (Royal Free Hospital, London, UK), David Hilton-Jones (John Radcliffe Hospital, Oxford, UK), Patrick Kiely (St George's Hospital, London, UK), Paul H. Plotz, Mark Gourley (National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD), and Hemlata Varsani (University College London, London, UK).

We thank members of the UK Adult Onset Myositis Immunogenetic Collaboration who recruited and enrolled subjects: Drs Yasmeen Ahmed (Llandudno General Hospital), Raymond Armstrong (Southampton General Hospital), Robert Bernstein (Manchester Royal Infirmary), Carol Black (Royal Free Hospital, London), Simon Bowman (University Hospital, Birmingham), Ian Bruce (Manchester Royal Infirmary), Robin Butler (Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry), John Carty (Lincoln County Hospital), Chandra Chattopadhyay (Wrightington Hospital), Easwaradhas Chelliah (Wrightington Hospital), Fiona Clarke (James Cook University Hospital, Middlesborough), Peter Dawes (Staffordshire Rheumatology Centre, Stoke on Trent), Joseph Devlin (Pinderfields General Hospital, Wakefield), Christopher Edwards (Southampton General Hospital), Paul Emery (Academic Unit of Musculoskeletal Disease, Leeds), John Fordham (South Cleveland Hospital, Middlesborough), Alexander Fraser (Academic Unit of Musculoskeletal Disease, Leeds), Hill Gaston (Addenbrooke's Hospital, Cambridge), Patrick Gordon (King's College Hospital, London), Bridget Griffiths (Freeman Hospital, Newcastle), Harsha Gunawardena (Frenchay Hospital, Bristol), Frances Hall (Addenbrooke's Hospital, Cambridge), Beverley Harrison (North Manchester General Hospital), Elaine Hay (Staffordshire Rheumatology Centre, Stoke on Trent), Lesley Horden (Dewsbury District General Hospital), John Isaacs (Freeman Hospital, Newcastle), Adrian Jones (Nottingham University Hospital), Sanjeet Kamath (Staffordshire Rheumatology Centre, Stoke on Trent), Thomas Kennedy (Royal Liverpool Hospital), George Kitas (Dudley Group Hospitals Trust, Birmingham), Peter Klimiuk (Royal Oldham Hospital), Sally Knights (Yeovil District Hospital, Somerset), John Lambert (Doncaster Royal Infirmary), Peter Lanyon (Queen's Medical Centre, Nottingham), Ramasharan Laxminarayan (Queen's Hospital, Burton Upon Trent), Bryan Lecky (Walton Neuroscience Centre, Liverpool), Raashid Luqmani (Nuffield Orthopaedic Centre, Oxford), Jeffrey Marks (Steeping Hill Hospital, Stockport), Michael Martin (St James University Hospital, Leeds), Dennis McGonagle (Academic Unit of Musculoskeletal Disease, Leeds), Neil McHugh (Royal National Hospital for Rheumatic Diseases, Bath), Francis McKenna (Trafford General Hospital, Manchester), John McLaren (Cameron Hospital, Fife), Michael McMahon (Dumfries & Galloway Royal Infirmary, Dumfries), Euan McRorie (Western General Hospital, Edinburgh), Peter Merry (Norfolk & Norwich University Hospital, Norwich), Sarah Miles (Dewsbury & District General Hospital, Dewsbury), James Miller (Royal Victoria Hospital, Newcastle), Anne Nicholls (West Suffolk Hospital, Bury St Edmunds), Jennifer Nixon (Countess of Chester Hospital, Chester), Voon Ong (Royal Free Hospital, London), Katherine Over (Countess of Chester Hospital, Chester), John Packham (Staffordshire Rheumatology Centre, Stoke on Trent), Nicolo Pipitone (King's College Hospital, London), Michael Plant (South Cleveland Hospital, Middlesborough), Gillian Pountain (Hinchingbrooke Hospital, Huntington), Thomas Pullar (Ninewells Hospital, Dundee), Mark Roberts (Salford Royal Foundation Trust), Paul Sanders (Wythenshawe Hospital, Manchester), David Scott (King's College Hospital, London), David Scott (Norfolk & Norwich University Hospital, Norwich), Michael Shadforth (Staffordshire Rheumatology Centre, Stoke on Trent), Thomas Sheeran (Cannock Chase Hospital, Cannock, Staffordshire), Arul Srinivasan (Broomfield Hospital, Chelmsford), David Swinson (Wrightington Hospital), Lee-Suan Teh (Royal Blackburn Hospital, Blackburn), Michael Webley (Stoke Manderville Hospital, Aylesbury), Brian Williams (University Hospital of Wales, Cardiff), and Jonathan Winer (Queen Elizabeth Hospital, Birmingham).

We thank members of the UK Juvenile Dermatomyositis Research Group who recruited and enrolled subjects: Dr Kate Armon, Mr Joe Ellis-Gage, Ms Holly Roper, Ms Vanja Briggs, and Ms Joanna Watts (Norfolk and Norwich University Hospitals); Dr Liza McCann, Mr Ian Roberts, Dr Eileen Baildam, Ms Louise Hanna, and Ms Olivia Lloyd (The Royal Liverpool Children’s Hospital, Alder Hey, Liverpool); Dr Phil Riley and Ms Ann McGovern (Royal Manchester Children’s Hospital, Manchester); Dr Clive Ryder, Mrs Janis Scott, Mrs Beverley Thomas, Professor Taunton Southwood, and Dr Eslam Al-Abadi (Birmingham Children’s Hospital, Birmingham); Dr Sue Wyatt, Mrs Gillian Jackson, Dr Tania Amin, Dr Mark Wood, Dr Vanessa Van Rooyen, and Ms Deborah Burton (Leeds General Infirmary, Leeds); Dr Joyce Davidson, Dr Janet Gardner-Medwin, Dr Neil Martin, Ms Sue Ferguson, Ms Liz Waxman, and Mr Michael Browne (The Royal Hospital for Sick Children, Yorkhill, Glasgow); Dr Mark Friswell, Professor Helen Foster, Mrs Alison Swift, Dr Sharmila Jandial, Ms Vicky Stevenson, Ms Debbie Wade, Dr Ethan Sen, Dr Eve Smith, Ms Lisa Qiao and Mr Stuart Watson (Great North Children’s Hospital, Newcastle); Dr Helen Venning, Dr Rangaraj Satyapal, Mrs Elizabeth Stretton, Ms Mary Jordan, Dr Ellen Mosley, Ms Anna Frost, Ms Lindsay Crate, and Dr Kishore Warrier (Queens Medical Centre, Nottingham); Professor Lucy Wedderburn, Dr Clarissa Pilkington, Dr N. Hasson, Mrs Sue Maillard, Ms Elizabeth Halkon, Ms Virginia Brown, Ms Audrey Juggins, Dr Sally Smith, Mrs Sian Lunt, Ms Elli Enayat, Mrs Hemlata Varsani, Miss Laura Kassoumeri, Miss Laura Beard, Miss Katie Arnold, Mrs Yvonne Glackin, Miss Stephanie Simou and Dr Beverley Almeida (Great Ormond Street Hospital, London); Dr Kevin Murray (Princess Margaret Hospital, Perth, Western Australia); Dr John Ioannou and Ms Linda Suffield (University College London Hospital); Dr Muthana Al-Obaidi, Ms Helen Lee, Ms Sam Leach and Ms Helen Smith (Sheffield’s Children’s Hospital); and Dr Nick Wilkinson, Ms Emma Inness, Ms Eunice Kendall and Mr David Mayers (Oxford University Hospitals).

We thank the following members of the US Childhood Myositis Heterogeneity Study Group who recruited and enrolled subjects: Drs Barbara S. Adams (University of Michigan, Ann Arbor, MI), Catherine A. Bingham (Hershey Medical Center, Hershey, PA), Gail D. Cawkwell (All Children's Hospital, St Petersburg, FL), Terri H. Finkel (Children's Hospital of Philadelphia, Philadelphia, PA), Steven W. George (Ellicott City, MD), Harry L. Gewanter (Richmond, VA), Ellen A. Goldmuntz (Children's National Medical Center, Washington, DC), Donald P. Goldsmith (St Christopher's Hospital for Children, Philadelphia, PA), Michael Henrickson (Children's Hospital, Madera, CA), Lisa Imundo (Columbia University, New York, NY), Ildy M. Katona (Uniformed Services University, Bethesda, MD), Carol B. Lindsley (University of Kansas, Kansas City), Chester P. Oddis (University of Pittsburgh, Pittsburgh, PA), Judyann C. Olson (Medical College of Wisconsin, Milwaukee), David Sherry (Children's Hospital of Philadelphia, Philadelphia, PA), Scott A. Vogelgesang (Walter Reed Army Medical Center, Washington, DC), Carol A. Wallace (Children's Medical Center, Seattle, WA), Patience H. White (George Washington University, Washington, DC) and Lawrence S. Zemel (Connecticut Children's Hospital, Hartford).

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Author notes

  1. F W Miller, W Chen, T P O'Hanlon, R G Cooper, J Vencovsky, L G Rider, K Danko, L R Wedderburn, I E Lundberg, L M Pachman, A M Reed, S R Ytterberg, L Padyukov, A Selva-O'Callaghan, T R Radstake, D A Isenberg, H Chinoy, W E R Ollier, P Scheet, B Peng, A Lee, J Byun, J A Lamb, P K Gregersen and C I Amos: F W Miller and W Chen: These authors contributed equally to this work.

  2. Other members of the Myositis Genetics Consortium (MYOGEN) are listed in the Acknowledgements.

Authors and Affiliations

  1. National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA

    F W Miller, T P O'Hanlon & L G Rider

  2. M.D. Anderson Cancer Center, Houston, TX, USA

    W Chen, P Scheet & B Peng

  3. MRC/ARUK Institute for Ageing and Chronic Disease, University of Liverpool, UK

    R G Cooper

  4. Institute of Rheumatology, Charles University, Prague, Czech Republic

    J Vencovsky

  5. 3rd Department of Internal Medicine, Division of Immunology University of Debrecen, Debrecen, Hungary

    K Danko

  6. Institute of Child Health, University College London, London, UK

    L R Wedderburn

  7. Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden

    I E Lundberg & L Padyukov

  8. Department of Pediatric Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    L M Pachman

  9. Mayo Clinic, Rochester, MN, USA

    A M Reed & S R Ytterberg

  10. Vall d'Hebron General Hospital, Barcelona, Spain

    A Selva-O'Callaghan

  11. Department of Rheumatology and Clinical Immunology, Laboratory for Translational Immunology, Utrecht University Medical Center; and Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands

    T R Radstake

  12. Division of Medicine, University College London, London, UK

    D A Isenberg

  13. The National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK

    H Chinoy

  14. Centre for Integrated Genomic Medical Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

    W E R Ollier & J A Lamb

  15. Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, USA

    A Lee & P K Gregersen

  16. Department of Community and Family Medicine, Dartmouth College, Hanover, NH, USA

    J Byun & C I Amos

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Miller, F., Chen, W., O'Hanlon, T. et al. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes. Genes Immun 16, 470–480 (2015). https://doi.org/10.1038/gene.2015.28

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