Meta-analyses uncover the genetic architecture of Idiopathic Inflammatory Myopathies.

Autor: Zhu C; Institute for Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Han Y; Institute for Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Byun J; Institute for Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Xiao X; Institute for Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., Rothwell S; Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Miller FW; Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland., Lundberg IE; Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Gregersen PK; The Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute, Manhasset, New York., Vencovsky J; Institute of Rheumatology and Department of Rheumatology, First Medical Faculty, Charles University, Prague, Czech Republic., Shaw VR; Institute for Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA., McHugh N; Department of Life Sciences, University of Bath, Bath, UK., Limaye V; Rheumatology Unit, Royal Adelaide Hospital and Discipline of Medicine, University of Adelaide, Adelaide, Australia., Selva-O'Callaghan A; Internal Medicine Department, Vall d'Hebron General Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain., Hanna MG; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK., Machado PM; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.; Centre for Rheumatology, UCL Division of Medicine, University College London, London, UK., Pachman LM; Division of Pediatric Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Reed AM; Department of Pediatrics, Duke University, Durham, North Carolina., Rider LG; Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland., Molberg Ø; Department of Rheumatology, Oslo University Hospital, Oslo, Norway., Benveniste O; Sorbonne Université, Assistance Publique Hôpitaux de Paris, Myology Research Center UMR974, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Paris, France., Radstake T; Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, the Netherlands., Doria A; Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy., De Bleecker JL; Department of Neurology, Ghent University, Ghent, Belgium., De Paepe B; Department of Neurology, Ghent University, Ghent, Belgium., Maurer B; Department of Rheumatology and Immunology, University Hospital, Bern, Switzerland., Ollier WE; Manchester Metropolitan University, School of Healthcare Sciences, Manchester, UK., Padyukov L; Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Wedderburn LR; NIHR Biomedical Research Centre at Great Ormond Street Hospital, Centre for Adolescent Rheumatology Versus Arthritis, and UCL Great Ormond Street Institute of Child Health, University College London, London, UK., Chinoy H; National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, UK, and Department of Rheumatology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, UK, and Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK., Lamb JA; Epidemiology and Public Health Group, Division of Population Health, Health Services Research & Primary Care, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK., Amos CI; Institute for Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.; Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Jazyk: angličtina
Zdroj: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2024 Dec 16. Date of Electronic Publication: 2024 Dec 16.
DOI: 10.1002/art.43088
Abstrakt: Objective: Idiopathic inflammatory myopathies (myositis, IIMs) are rare, systemic autoimmune disorders that lead to muscle inflammation, weakness, and extra-muscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis dataset to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes.
Methods: We performed association analyses on 14,903 individuals (3,206 cases and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine (TOPMed) reference panel. Fine-mapping and expression quantitative trait locus co-localization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities.
Results: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-tRNA synthetase autoantibodies (anti-Jo1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in EBV-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation.
Conclusion: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.
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Databáze: MEDLINE
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