Association with HLA-DRβ1 position 37 distinguishes juvenile Dermatomyositis from adult-onset myositis

Claire T. Deakin, Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
John Bowes, Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Lisa G. Rider, Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland, USA.
Frederick W. Miller, Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland, USA.
Lauren M. Pachman, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
Helga Sanner, Department of Rheumatology, University of Oslo, Oslo, Norway.
Kelly Rouster-Stevens, Emory University School of Medicine, Atlanta, Georgia, USA.
Gulnara Mamyrova, Division of Rheumatology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Rodolfo Curiel, Division of Rheumatology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Brian M. Feldman, Division of Rheumatology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Adam M. Huber, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
Ann M. Reed, Pediatrics, Duke University, Durham, North Carolina, USA.
Heinrike Schmeling, Alberta Children's Hospital and Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.
Charlotte G. Cook, Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
Lucy R. Marshall, Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
Meredyth G. Wilkinson, Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
Stephen Eyre, Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Soumya Raychaudhuri, Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Lucy R. Wedderburn, Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.

Document Type

Journal Article

Publication Date

1-31-2022

Journal

Human molecular genetics

DOI

10.1093/hmg/ddac019

Abstract

OBJECTIVES: Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease and the most common idiopathic inflammatory myopathy (IIM) of children. JDM and adult-onset dermatomyositis (DM) have similar clinical, biological and serological features, although these features differ in prevalence between childhood-onset and adult-onset disease, suggesting age of disease onset may influence pathogenesis. Therefore, a JDM-focused genetic analysis was performed using the largest collection of JDM samples to date. METHODS: Caucasian JDM samples (n = 952) obtained via international collaboration were genotyped using the Illumina HumanCoreExome chip. Additional non-assayed HLA loci and genome-wide SNPs were imputed. RESULTS: HLA-DRB1*03:01 was confirmed as the classical HLA allele most strongly associated with JDM (OR 1.66; 95% CI 1.46, 1.89; P = 1.4 × 10-14), with an independent association at HLA-C*02:02 (OR = 1.74; 95% CI 1.42, 2.13, P = 7.13 × 10-8). Analyses of amino acid positions within HLA-DRB1 indicated the strongest association was at position 37 (omnibus P = 3.3 × 10-19), with suggestive evidence this association was independent of position 74 (omnibus P = 5.1 × 10-5), the position most strongly associated with adult-onset DM. Conditional analyses also suggested the association at position 37 of HLA-DRB1 was independent of some alleles of the Caucasian HLA 8.1 ancestral haplotype (AH8.1) such as HLA-DQB1*02:01 (OR = 1.62; 95% CI 1.36, 1.93; P = 8.70 × 10-8), but not HLA-DRB1*03:01 (OR = 1.49; 95% CR 1.24, 1.80; P = 2.24 × 10-5). No associations outside the HLA region were identified. CONCLUSIONS: Our findings confirm previous associations with AH8.1 and HLA-DRB1*03:01, HLA-C*02:02 and identify a novel association with amino acid position 37 within HLA-DRB1 which may distinguish JDM from adult DM.

Department

Medicine

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