Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases

• Type of Material: Article
• Authors: A Hinks, University of Manchester; J Bowes, University of Manchester; J Cobb, University of Manchester; HC Ainsworth, Wake Forest University; MC Marion, Wake Forest University; ME Comeau, Wake Forest University; M Sudman, Cincinnati Children's Hospital Medical Center; B Han, Harvard Medical School; ML Becker, Children's Mercy-Kansas City; JF Bohnsack, University of Utah; PIW de Bakker, University Medical Center Utrecht; JP Haas, German Center for Pediatric and Adolescent Rheumatology; M Hazen, Boston Children's Hospital; DJ Lovell, Cincinnati Children's Hospital Medical Center; PA Nigrovic, Boston Children's Hospital; E Nordal, University Hospital of North Norway, and UIT The Arctic University of Norway; M Punnaro, Arthritis Clinic Texas Scottish Rite Hospital for Children; AM Rosenberg, University of Saskatchewan; M Rygg, NTNU Norwegian Univ Sci & Technol; SL Smith, University of Manchester; CA Wise, Texas Scottish Rite Hosp Children; V Videm, NTNU - Norwegian University of Science and Technology; LR Wedderburn, University College London; A Yarwood, University of Manchester; RSM Yeung, The Hospital for Sick Children and University of Toronto; Sampath Prahalad, Emory University; CD Langefeld, Wake Forest University; S Raychaudhuri, University of Manchester; SD Thompson, Cincinnati Children's Hospital Medical Center; W Thomson, University of Manchester
• Language: English
• Date: 2017-04-01
• Publisher: BMJ Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Published by the BMJ Publishing Group Limited.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/annrheumdis-2016-210025
• Title of Journal or Parent Work: Annals of the Rheumatic Diseases
• ISSN: 0003-4967
• Volume: 76
• Issue: 4
• Start Page: 765
• End Page: 772
• Grant/Funding Information: Wellcome Trust (068545/Z/01, 076113/C/04/Z); for statistical support at Wake-Forest, National Institutes of Health (NIH) grant (R01-AR-057106); National Institute for Health Research programme grant, (RP-PG-0310-1002); Doris Duke Charitable Foundation Grant (2013097); NIH (10.13039/100000002, U01 DK062418, RC2AR059092, DK062431, DK062422, DK0); for Utah samples, NIH grants (K23-AR-50177 and R01-AR-060893; UK samples, Sparks UK (08ICH09); for the UK samples and support, Arthritis Research UK (20385 and 20542); Medical Research Council (G0000934, MR/M004600/1); Canadian Institutes of Health Research (FRN-82517); the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology; NIH Federal Ministry of Education and Research, Germany (01GM0907 and 01 ZZ 0403); SR is supported by grants from the NIH (1R01AR063759); genotyping of the US JIA, German JIA and respective control collections was supported by NIAMS/NIGMS/NIAID/NIH (RC1-AR-058587, U01-AI-067150S1, N01-AR-42272, P01); Juvenile Diabetes Research Foundation International; the US sample recruitment was supported in part by NIAMS/NIGMS/NIAID/NIH and from Texas Scottish Rite Hospital for Children (N01AR62277, GM103510, AI082714, AR053483, 1296353. Patient recruitment and DNA preparation in Canada was supported by funding from the Canadian Institutes of Health Research (FRN-82517), the Canadian Arthritis Society and the Canadian Arthritis Network.
• Keywords: SUSCEPTIBILITY LOCI; Life Sciences & Biomedicine; SEROPOSITIVE RHEUMATOID-ARTHRITIS; RISK; Rheumatology; ASSOCIATION; Science & Technology; ALLELES; HLA-DQ; INSIGHTS
• Research Categories: Health Sciences, Pharmacology; Biology, Genetics

Abstract

Objectives: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. Methods: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14â €..390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. Results: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. Conclusions: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.