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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Neurotherapeutics Open Access 08 April 2022
Subscribe to Journal
Get full journal access for 1 year
only $14.88 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Parkes M, Cortes A, van Heel DA, Brown MA . Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 2013; 14: 661–673.
Ricano-Ponce I, Wijmenga C . Mapping of immune-mediated disease genes. Annu Rev Genomics Hum Genet 2013; 14: 325–353.
Rider LG, Miller FW . Deciphering the clinical presentations, pathogenesis, and treatment of the idiopathic inflammatory myopathies. JAMA 2011; 305: 183–190.
Ginn LR, Lin JP, Plotz PH, Bale SJ, Wilder RL, Mbauya A et al. Familial autoimmunity in pedigrees of idiopathic inflammatory myopathy patients suggests common genetic risk factors for many autoimmune diseases. Arthritis Rheum 1998; 41: 400–405.
Niewold TB, Wu SC, Smith M, Morgan GA, Pachman LM . Familial aggregation of autoimmune disease in juvenile dermatomyositis. Pediatrics 2011; 127: e1239–e1246.
Scott AP, Laing NG, Mastaglia F, Needham M, Walter MC, Dalakas MC et al. Recombination mapping of the susceptibility region for sporadic inclusion body myositis within the major histocompatibility complex. J Neuroimmunol 2011; 235: 77–83.
O'Hanlon TP, Carrick DM, Targoff IN, Arnett FC, Reveille JD, Carrington M et al. Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies. Medicine (Baltimore) 2006; 85: 111–127.
Chinoy H, Salway F, Fertig N, Shephard N, Tait BD, Thomson W et al. In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype. Arthritis Res Ther 2006; 8: R13.
Trowsdale J, Knight JC . Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet 2013; 14: 301–323.
Horton R, Gibson R, Coggill P, Miretti M, Allcock RJ, Almeida J et al. Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project. Immunogenetics 2008; 60: 1–18.
Miller FW Inflammatory myopathies: polymyositis, dermatomyositis, and related conditions. In: Koopman W, Moreland L (eds.) Arthritis and Allied Conditions, A Textbook of Rheumatology; Vol 15. Lippincott, Williams and Wilkins:: Philadelphia, 2005: 1593–1620.
Meyer A, Meyer N, Schaeffer M, Gottenberg JE, Geny B, Sibilia J . Incidence and prevalence of inflammatory myopathies: a systematic review. Rheumatology(Oxford) 2015; 54: 50–63.
Miller FW, Cooper RG, Vencovsky J, Rider LG, Danko K, Wedderburn LR et al. Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. Arthritis Rheum 2013; 65: 3239–3247.
Mitchell MK, Gregersen PK, Johnson S, Parsons R, Vlahov D New York Cancer P. The New York Cancer Project: rationale, organization, design, and baseline characteristics. J Urban Health 2004; 81: 301–310.
Wellcome Trust Case Control C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661–678.
Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J Med 2007; 357: 1199–1209.
O'Hanlon TP, Miller FW . Genetic risk and protective factors for the idiopathic inflammatory myopathies. Curr Rheumatol Rep 2009; 11: 287–294.
Chinoy H, Lamb JA, Ollier WE, Cooper RG . Recent advances in the immunogenetics of idiopathic inflammatory myopathy. Arthritis Res Ther 2011; 13: 216.
Chinoy H, Payne D, Poulton KV, Fertig N, Betteridge Z, Gunawardena H et al. HLA-DPB1 associations differ between DRB1*03 positive anti-Jo-1 and anti-PM-Scl antibody positive idiopathic inflammatory myopathy. Rheumatology (Oxford) 2009; 48: 1213–1217.
Pinto D, Darvishi K, Shi X, Rajan D, Rigler D, Fitzgerald T et al. Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat Biotechnol 2011; 29: 512–520.
Hassan AB, Nikitina-Zake L, Sanjeevi CB, Lundberg IE, Padyukov L . Association of the proinflammatory haplotype (MICA5.1/TNF2/TNFa2/DRB1*03) with polymyositis and dermatomyositis. Arthritis Rheum 2004; 50: 1013–1015.
Love LA, Leff RL, Fraser DD, Targoff IN, Dalakas M, Plotz PH et al. A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine (Baltimore) 1991; 70: 360–374.
Miller FW . Myositis-specific autoantibodies. Touchstones for understanding the inflammatory myopathies. JAMA 1993; 270: 1846–1849.
Rider LG, Shah M, Mamyrova G, Huber AM, Rice MM, Targoff IN et al. The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies. Medicine (Baltimore) 2013; 92: 223–243.
Casciola-Rosen L, Mammen AL . Myositis autoantibodies. Curr Opin Rheumatol 2012; 24: 602–608.
Scheet P, Stephens M . A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 2006; 78: 629–644.
Candore G, Lio D, Colonna RG, Caruso C . Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: effect of multiple gene interactions. Autoimmun Rev 2002; 1: 29–35.
Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev 1999; 167: 257–274.
Chinoy H, Salway F, John S, Fertig N, Tait BD, Oddis CV et al. Tumour necrosis factor-alpha single nucleotide polymorphisms are not independent of HLA class I in UK Caucasians with adult onset idiopathic inflammatory myopathies. Rheumatology (Oxford) 2007; 46: 1411–1416.
Chinoy H, Adimulam S, Marriage F, New P, Vincze M, Zilahi E et al. Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study. Ann Rheum Dis 2012; 71: 961–965.
Rothwell S, Cooper RG, Lamb JA, Chinoy H . Entering a new phase of immunogenetics in the idiopathic inflammatory myopathies. Curr Opin Rheumatol 2013; 25: 735–741.
Kaslow RA, Shaw S . The role of histocompatibility antigens (HLA) in infection. Epidemiol Rev 1981; 3: 90–114.
Xie Z, Chang C, Zhou Z . Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol 2014; 47: 174–192.
Candore G, Campagna AM, Cuppari I, Di CD, Mineo C, Caruso C . Genetic control of immune response in carriers of the 8.1 ancestral haplotype: correlation with levels of IgG subclasses: its relevance in the pathogenesis of autoimmune diseases. Ann NY Acad Sci 2007; 1110: 151–158.
Candore G, Balistreri CR, Campagna AM, Colombo A, Cuppari I, Di-Carlo D et al. Genetic control of immune response in carriers of ancestral haplotype 8.1: the study of chemotaxis. Ann NY Acad Sci 2006; 1089: 509–515.
Olivares M, Laparra JM, Sanz Y . Host genotype, intestinal microbiota and inflammatory disorders. Br J Nutr 2013; 109: S76–S80.
Olivares M, Neef A, Castillejo G, Palma GD, Varea V, Capilla A et al. The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease. Gut 2014; 64: 406–417.
Bohan A, Peter JB, Bowman RL, Pearson CM . Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore) 1977; 56: 255–286.
Targoff IN, Trieu EP, Miller FW . Reaction of anti-OJ autoantibodies with components of the multi- enzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase. J Clin Invest 1993; 91: 2556–2564.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Rich SS, Concannon P, Erlich H, Julier C, Morahan G, Nerup J et al. The Type 1 Diabetes Genetics Consortium. Ann NY Acad Sci 2006; 1079: 1–8.
Erlich HA, Lohman K, Mack SJ, Valdes AM, Julier C, Mirel D et al. Association analysis of SNPs in the IL4R locus with type I diabetes. Genes Immun 2009; 10: S33–S41.
Concannon P, Chen WM, Julier C, Julier C, Morahan G, Akolkar B et al. Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium. Diabetes 2009; 58: 1018–1022.
Purcell S, Cherny SS, Sham PC . Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.
Evangelou E, Ioannidis JP . Meta-analysis methods for genome-wide association studies and beyond. Nat Rev Genet 2013; 14: 379–389.
Begum F, Ghosh D, Tseng GC, Feingold E . Comprehensive literature review and statistical considerations for GWAS meta-analysis. Nucleic Acids Res 2012; 40: 3777–3784.
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).
The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the institutions with which they are affiliated.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Genes and Immunity website
About this article
Cite this article
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
This article is cited by
Human leukocyte antigen (HLA) haplotype matching in unrelated single HLA allele mismatch bone marrow transplantation
Bone Marrow Transplantation (2022)
Zeitschrift für Rheumatologie (2022)
Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
Nature Genetics (2021)