Identification and evaluation of 41 risk loci for juvenile idiopathic arthritis informs precision medicine: mechanistic implications of DNA topology and an HLA-A*02:01-ERAP2 interaction
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT Juvenile idiopathic arthritis (JIA), the most common class of pediatric rheumatic diseases, can lead to joint damage and extra-articular features including uveitis. Early treatment can improve functional outcomes; but many patients do not respond to first-line treatments. We present a JIA Immunochip-based association analysis of rheumatoid factor-negative polyarticular JIA and oligoarticular JIA. This study spans 3,939 cases and 14,412 controls, including 1,123 cases and 1,356 controls not previously analyzed. We identify 41 (14 novel) JIA risk regions and report a JIA polygenic risk score that also associates with age of onset. Functional mechanisms presented include: a novel interaction between HLA-A*02:01 and ERAP2 , cluster-based approach for functional amino acid discovery within HLA-DRB1, and sequence-dependent DNA topology for variant prioritization. We present a comprehensive list of curated gene-drug/small molecule interactions for clinically focused studies. These findings provide a deepened understanding of the genetics of JIA and potential mechanisms to inform precision medicine.
Source: medRxiv
Authors: Hannah C. Ainsworth, Ekaterina S. Khvatkova, Marc Sudman, Miranda C. Marion, Kaiyu Jiang, John F. Bohnsack, Mary E. Comeau, Patrick M. Gaffney, Johannes-Peter Haas, Timothy D. Howard, Kimme Hyrich, Judith A. James, Peter A. Nigrovic, Ellen B. Nordal, Alan M. Rosenberg, Marite Rygg, Samantha L. Smith, Vibeke Videm, Lucy R. Wedderburn, Carol A. Wise, Rae S.M. Yeung, Susan D. Thompson, Grant S. Schulert, Sampath Prahalad, John Bowes, Sheila T. Angeles-Han, James N. Jarvis, Carl D. Langefeld
Institutions: Wake Forest University Health Sciences, Wake Forest University, Cincinnati Children's Hospital Medical Center, University of Washington, University of Utah, Oklahoma Medical Research Foundation, German Center for Pediatric and Adolescent Rheumatology, Manchester Academic Health Science Centre, University of Manchester, Manchester University NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, University of Oklahoma Health Sciences Center, Brigham and Women's Hospital, Boston Children's Hospital, Harvard University, University Hospital of North Norway, UiT The Arctic University of Norway, University of Saskatchewan, Norwegian University of Science and Technology, St Olav's University Hospital, Great Ormond Street Hospital, NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, Texas Scottish Rite Hospital for Children, The University of Texas Southwestern Medical Center, University of Toronto, Hospital for Sick Children, University of Cincinnati, Emory University, Children's Healthcare of Atlanta
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Cincinnati Children's Hospital Medical Center, Norges Teknisk-Naturvitenskapelige Universitet, Arthritis Society, National Institute for Health and Care Research, Ministry of Education, India, Helse Midt-Norge, Helse Nord RHF, Versus Arthritis, National Institutes of Health, Manchester Biomedical Research Centre, Faculty of Medicine and Health, University of Sydney, National Eye Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1155020941, G1483213741, G1798610363, Genetics of Juvenile Idiopathic Arthritis and Subtypes, G2394657754, Gene Expression in Pediatric Arthritis, Defining the complex genetics of JIA, G6694894702, G6882471458, Centre for Genetics and Genomics Arthritis UK, Predicting uveitis onset in children with juvenile idiopathic arthritis, Epigenetic Mechanisms That Drive Genetic Risk in Juvenile Arthritis, Cincinnati Rheumatic Diseases Resource Center, Oklahoma Rheumatic Disease Research Cores Center, Joint Biology Consortium Resource-based Center, Bridging the gap between GWAS and mechanism in arthritis
OpenAlex ID: W7213554936