The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis

• Type of Material: Article
• Authors: Anne Hinks, University of Manchester; Miranda C. Marion, Wake Forest University; Joanna Cobb, University of Manchester; Mary E. Comeau, Wake Forest University; Marc Sudman, Cincinnati Children's Hospital Medical Center; Hannah C. Ainsworth, Wake Forest University; John Bowes, University of Manchester; Mara L. Becker, Childrens Mercy Kansas City; John F. Bohnsack, University of Utah; Johannes‐Peter Haas, German Centre for Pediatric and Adolescent Rheumatology; Daniel J. Lovell, Cincinnati Children's Hospital Medical Center; Elizabeth D. Mellins, Stanford University; J. Lee Nelson, University of Washington; Ellen Nordal, The Arctic University of Norway; Marilynn Punaro, University of Texas; Ann M. Reed, Duke University; Carlos D. Rose, DuPont Children's Hospital; Alan M. Rosenberg, University of Saskatchewan; Marite Rygg, Norwegian University of Science and Technology; Samantha L. Smith, University of Manchester; Anne M. Stevens, University of Washington; Vibeke Videm, Norwegian University of Science and Technology; Carol A. Wallace, Seattle Childrens Hosp & Res Inst; Lucy R. Wedderburn, University College London; Annie Yarwood, University of Manchester; Rae S. M. Yeung, University of Toronto; Carl D. Langefeld, Wake Forest University; Susan D. Thompson, Cincinnati Children's Hospital Medical Center; Wendy Thomson, University of Manchester; Sampath Prahalad, Emory University
• Language: English
• Date: 2018-06-06
• Publisher: Wiley: 12 months
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors.Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/art.40443
• Title of Journal or Parent Work: Arthritis and Rheumatology
• ISSN: 2326-5191
• Volume: 70
• Issue: 6
• Start Page: 957
• End Page: 962
• Grant/Funding Information: The Childhood Arthritis Prospective Study was funded by Arthritis Research UK (grant 20542).; Patient recruitment and DNA preparation in Canada was supported by the Canadian Institutes of Health Research (grant FRN‐82517), the Canadian Arthritis Society, and the Canadian Arthritis Network.; Genotyping of the UK JIA case samples was supported by Arthritis Research UK (grant 20385).; The Federal Ministry of Education and Research, Germany supported patient recruitment and sample preparation in Germany (BMBF grants 01GM0907 and 01 ZZ 0403).; See publication for full funding statement.; Support for computing resources and data analysis was provided by the Wake Forest School of Medicine Center for Public Health Genomics and the NIH (CSR grant R01‐AR‐057106).; The Childhood Arthritis Response to Medication Study was funded by Sparks UK (grant 08ICH09), Arthritis Research UK (grant 20164), and the Medical Research Council (grant MR/M004600/1) and supported by the NIHR Biomedical Research Centres at Great Ormond Street Hospital for Children NHS Foundation Trust, University College London Hospitals Trust, and the NIHR Clinical Research Network.; Genotyping of the US juvenile idiopathic arthritis (JIA), German JIA, and respective control collections was supported by the NIH (Center for Scientific Review [CSR] grants RC1‐AR‐058587 and U01‐AI‐067150S1).; Genotyping of control samples was supported, in part, by the Juvenile Diabetes Research Foundation International and the NIH (CSR grant U01‐DK‐062418).; Sample recruitment was supported in part by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grants N01‐AR‐62277 and AR‐053483, National Institute of General Medical Sciences grant GM‐103510, and National Institute of Allergy and Infectious Diseases grant AI‐082714) and by the Texas Scottish Rite Hospital for Children (grant 1296353).; The Nord‐Trøndelag Health (HUNT) Study, which contributed control samples, is a collaboration between the HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology), Nord‐Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health and was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology.; Patient recruitment and DNA preparation in the US were largely funded by the NIH (CSR grants N01‐AR‐42272, P01‐AR‐048929, P30‐AR‐473639, K23‐AR‐50177, and R01‐AR‐060893), with contributions from the Rheumatology Research Foundation, the Arthritis Foundation, the Val A. Browning Charitable Foundation (Salt Lake City, UT), and the Marcus Foundation, Inc. (Atlanta, GA).
• Keywords: ASSOCIATION; MHC; Rheumatology; RISK; Science & Technology; Life Sciences & Biomedicine; SUSCEPTIBILITY LOCI; HLA
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)–positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies. Methods: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA. Results: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10−31). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16–29 years than to that of RA patients with age at onset ≥70 years. Conclusion: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.