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Ann Rheum Dis. 2017 May;76(5):906-913. doi: 10.1136/annrheumdis-2016-210324. Epub 2016 Dec 7.

Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.

Author information

1
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.
2
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.
3
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, Manchester, UK.
4
Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, UK.
5
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
6
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
7
Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.
8
Department of Pediatrics, University of Genova, Genoa, Italy.
9
Pediatrics II Unit, Giannina Gaslini Institute, Genoa, Italy.
10
Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
11
Departments of Pediatrics and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
12
Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
13
Department of Pediatrics, Cleveland Clinic, Cleveland, Ohio, USA.
14
Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
15
Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA.
16
Department of Pediatrics, Stanford University, Stanford, California, USA.
17
Service of Immunology and Rheumatology, Hospital de Pediatria Garrahan, Buenos Aires, Argentina.
18
Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil.
19
Universidade Federal de Rio de Janeiro, Rio de Janeiro, Brazil.
20
Department of Pediatrics, University of Toronto, Toronto, Canada.
21
Department of Immunology, University of Toronto, Toronto, Canada.
22
Institute of Medical Science, University of Toronto, Toronto, Canada.
23
Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada.
24
Institute of Child Health, University College London, London, UK.
25
Center of Paediatric and Adolescent Rheumatology, University College London, London, UK.
26
Pediatric Rheumatology Unit, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.
27
German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.
28
University Hospital Cal Gustav Carus, Dresden, Germany.
29
Department of Rheumatology and Clinical Immunology, Charité -University Medicine, Berlin, Germany.
30
Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany.
31
Department of Pediatrics, RWTH Aachen University, Aachen, Germany.
32
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.
33
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
34
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
35
Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA.
36
Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA.
37
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
38
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
39
Center for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Government, Granada, Spain.
40
Unit of Chronic Inflammatory Diseases, Institute for Environmental Medicine, Karolinska Institutet, Solna, Sweden.
41
Interdisciplinary Cluster for Applied Genoproteomics-Université de Liège, Liège, Belgium.
42
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
43
Sidra Medical and Research Centre, Doha, Qatar.
44
Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
45
Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.

Abstract

OBJECTIVES:

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.

KEYWORDS:

Adult Onset Still's Disease; Gene Polymorphism; Juvenile Idiopathic Arthritis

PMID:
27927641
PMCID:
PMC5530341
DOI:
10.1136/annrheumdis-2016-210324
[Indexed for MEDLINE]
Free PMC Article

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