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Extended report
Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases
  1. A Hinks1,
  2. J Bowes1,
  3. J Cobb1,2,
  4. H C Ainsworth3,
  5. M C Marion3,
  6. M E Comeau3,
  7. M Sudman4,
  8. B Han5,6,
  9. Juvenile Arthritis Consortium for Immunochip,
  10. M L Becker7,
  11. J F Bohnsack8,
  12. P I W de Bakker9,
  13. J P Haas10,
  14. M Hazen11,
  15. D J Lovell12,
  16. P A Nigrovic11,13,
  17. E Nordal14,
  18. M Punnaro15,16,
  19. A M Rosenberg17,
  20. M Rygg18,
  21. S L Smith1,
  22. C A Wise19,20,
  23. V Videm18,
  24. L R Wedderburn21,22,
  25. A Yarwood1,
  26. R S M Yeung23,
  27. S Prahalad24,
  28. C D Langefeld3,
  29. S Raychaudhuri1,5,25,26,
  30. S D Thompson4,
  31. W Thomson1,2
  1. 1Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Manchester, UK
  2. 2NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  3. 3Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
  4. 4Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  5. 5Divisions of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
  6. 6Department of Convergence Medicine, University of Ulsan College of Medicine & Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
  7. 7Division of Rheumatology and Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy-Kansas City, Kansas City, Missouri, USA
  8. 8Division of Allergy, Immunology and Paediatric Rheumatology, University of Utah, Salt Lake City, Utah, USA
  9. 9Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
  10. 10German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany
  11. 11Division of Immunology, Department of Rheumatology, Boston Children's Hospital, Boston, Massachusetts, USA
  12. 12Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  13. 13Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
  14. 14Department of Paediatrics, University Hospital of North Norway, and UIT The Arctic University of Norway, Tromsø, Norway
  15. 15Arthritis Clinic Texas Scottish Rite Hospital for Children, Dallas, Texas, USA
  16. 16Department of Paediatrics, UT Southwestern Medical Center, Dallas, Texas, USA
  17. 17Division of Rheumatology, Department of Paediatrics, University of Saskatchewan, Saskatoon, Canada
  18. 18Department of Laboratory Medicine, Children's and Women's Health, NTNU - Norwegian University of Science and Technology, and St. Olavs University Hospital, Trondheim, Norway
  19. 19Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA
  20. 20Department of Orthopaedic Surgery, Paediatrics, and McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas, USA
  21. 21Arthritis Research UK Centre for Adolescent Rheumatology, UCL GOS Institute of Child Health, University College London, London, UK
  22. 22NIHR-Great Ormond Street Hospital Biomedical Research Centre, London, UK
  23. 23The Hospital for Sick Children and University of Toronto, Toronto, Canada
  24. 24Department of Paediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, USA
  25. 25Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA
  26. 26Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
  1. Correspondence to Dr Anne Hinks, Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK; Anne.Hinks{at}manchester.ac.uk

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 14 390 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.

  • Juvenile Idiopathic Arthritis
  • Autoimmune Diseases
  • Rheumatoid Arthritis
  • Gene Polymorphism

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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Footnotes

  • Handling editor Tore K Kvien

  • AH and JB contributed equally.

  • SDT and WT contributed equally as senior authors.

  • Twitter Follow Paul de Bakker @Piwdb, Soumya Raychaudhuri @soumya_boston and University of Manchester, Centre for Musculoskeletal disease @UoMMskResearch

  • Contributors WT, SDT, SR, CDL, SP, JB and AH led the study. AH, JB, SR, CDL, SP, SDT and WT wrote the paper. AH, JB, JC, HCA, MCM, MEC, MS, BH, CDL and SR performed the data and statistical analysis. MLB, JFB, PIWdB, JPH, MH, DJL, PAN, EN, MP, AMR, MR, SLS, CAW, VV, LRW, AY, RSMY contributed to the patient ascertainment, sample collection and/or genotyping. All authors reviewed the final manuscript.

  • Collaborators Juvenile Arthritis Consortium for Immunochip: full list of affiliations for consortia will appear in the online supplementary information.

  • Funding 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.

  • Competing interests LRW reports Honorarium for speaker at Symposium from Pfizer Inc. SP has been on advisory boards for Novartis, medac and UCB pharma. None of these had any bearing on the work reported in this publication.

  • Ethics approval North-West Multi-Centre Research Ethics Committee (MREC 99/8/84), the University of Manchester Committee on the Ethics of Research on Human Beings and National Research Ethics Service (NRES 02/8/104).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Additional data are included in the online supplementary data.

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