title: Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.
abstract: OBJECTIVE
  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.
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Hinks
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Manchester, UK.
authors.forename: J
authors.identifier: http://orcid.org/0000-0003-4659-031X
authors.initials: J
authors.lastname: Bowes
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Manchester, UK.|NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Cobb
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Ainsworth
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Marion
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Comeau
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sudman
authors.affiliation: Divisions of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.|Department of Convergence Medicine, University of Ulsan College of Medicine & Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: B
authors.initials: B
authors.lastname: Han
authors.affiliation: Division of Rheumatology and Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy-Kansas City, Kansas City, Missouri, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Becker
authors.affiliation: Division of Allergy, Immunology and Paediatric Rheumatology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Bohnsack
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: P I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.
authors.forename: J P
authors.initials: JP
authors.lastname: Haas
authors.affiliation: Division of Immunology, Department of Rheumatology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hazen
authors.affiliation: Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lovell
authors.affiliation: Division of Immunology, Department of Rheumatology, Boston Children's Hospital, Boston, Massachusetts, USA.|Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Nigrovic
authors.affiliation: Department of Paediatrics, University Hospital of North Norway, and UIT The Arctic University of Norway, Tromsø, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Nordal
authors.affiliation: Arthritis Clinic Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.|Department of Paediatrics, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Punnaro
authors.affiliation: Division of Rheumatology, Department of Paediatrics, University of Saskatchewan, Saskatoon, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Rosenberg
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, NTNU - Norwegian University of Science and Technology, and St. Olavs University Hospital, Trondheim, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Rygg
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Manchester, UK.
authors.forename: S L
authors.identifier: http://orcid.org/0000-0002-4108-8497
authors.initials: SL
authors.lastname: Smith
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.|Department of Orthopaedic Surgery, Paediatrics, and McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Wise
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, NTNU - Norwegian University of Science and Technology, and St. Olavs University Hospital, Trondheim, Norway.
authors.forename: V
authors.initials: V
authors.lastname: Videm
authors.affiliation: Arthritis Research UK Centre for Adolescent Rheumatology, UCL GOS Institute of Child Health, University College London, London, UK.|NIHR-Great Ormond Street Hospital Biomedical Research Centre, London, UK.
authors.forename: L R
authors.initials: LR
authors.lastname: Wedderburn
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Yarwood
authors.affiliation: The Hospital for Sick Children and University of Toronto, Toronto, Canada.
authors.forename: R S M
authors.initials: RS
authors.lastname: Yeung
authors.affiliation: Department of Paediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, USA.
authors.forename: S
authors.initials: S
authors.lastname: Prahalad
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Manchester, UK.|Divisions of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA.|Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Thompson
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, University Of Manchester, Manchester, UK.|NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: W
authors.initials: W
authors.lastname: Thomson
mesh_terms: D000328:Adult; D000483:Alleles; D000596:Amino Acids; D001171:Arthritis, Juvenile / Q000145:classification / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012217:Rheumatoid Factor / Q000235:genetics*
chemical_list: D000596:Amino Acids; D006680:HLA Antigens; D059811:HLA-DRB1 Chains; D012217:Rheumatoid Factor
keywords: Autoimmune Diseases; Gene Polymorphism; Juvenile Idiopathic Arthritis; Rheumatoid Arthritis