title: Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.
abstract: OBJECTIVE
  Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA.
  
  
  METHODS
  We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes.
  
  
  RESULTS
  The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes.
  
  
  CONCLUSIONS
  The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.
authors.affiliation: Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ombrello
authors.affiliation: Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Arthur
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Hinks
authors.affiliation: Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tachmazidou
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.|Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Grom
authors.affiliation: Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.affiliation: Department of Pediatrics, University of Genova, Genoa, Italy.|Pediatrics II Unit, Giannina Gaslini Institute, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.affiliation: Pediatrics II Unit, Giannina Gaslini Institute, Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
authors.forename: Seza
authors.initials: S
authors.lastname: Özen
authors.affiliation: Departments of Pediatrics and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.|Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: Sampath
authors.initials: S
authors.lastname: Prahalad
authors.affiliation: Department of Pediatrics, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Zeft
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Bohnsack
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA.
authors.forename: Norman T
authors.initials: NT
authors.lastname: Ilowite
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.affiliation: Service of Immunology and Rheumatology, Hospital de Pediatria Garrahan, Buenos Aires, Argentina.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Claudio
authors.initials: C
authors.lastname: Len
authors.affiliation: Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Maria Odete E
authors.initials: MO
authors.lastname: Hilario
authors.affiliation: Universidade Federal de Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Sheila
authors.initials: S
authors.lastname: Oliveira
authors.affiliation: Department of Pediatrics, University of Toronto, Toronto, Canada.|Department of Immunology, University of Toronto, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Rae S M
authors.initials: RS
authors.lastname: Yeung
authors.affiliation: Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Rosenberg
authors.affiliation: Institute of Child Health, University College London, London, UK.|Center of Paediatric and Adolescent Rheumatology, University College London, London, UK.
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
authors.affiliation: Pediatric Rheumatology Unit, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Anton
authors.affiliation: German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Haas
authors.affiliation: University Hospital Cal Gustav Carus, Dresden, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Rosen-Wolff
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité -University Medicine, Berlin, Germany.|Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Minden
authors.affiliation: Department of Pediatrics, RWTH Aachen University, Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Tenbrock
authors.affiliation: Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
authors.forename: Erkan
authors.initials: E
authors.lastname: Demirkaya
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, Manchester, UK.|National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Cobb
authors.affiliation: Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Baskin
authors.affiliation: Department of Pediatrics, University of Genova, Genoa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Signa
authors.affiliation: Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Shuldiner
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.affiliation: Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Achkar
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.|Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.|Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Leah C
authors.identifier: http://orcid.org/0000-0003-3979-2220
authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Center for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Government, Granada, Spain.|Unit of Chronic Inflammatory Diseases, Institute for Environmental Medicine, Karolinska Institutet, Solna, Sweden.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics-Université de Liège, Liège, Belgium.|Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Docampo
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.|Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.affiliation: Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Gül
authors.affiliation: Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.|Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.affiliation: Center of Paediatric and Adolescent Rheumatology, University College London, London, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Woo
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, Manchester, UK.|National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
mesh_terms: D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000235:genetics*; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
keywords: Adult Onset Still's Disease; Gene Polymorphism; Juvenile Idiopathic Arthritis