Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.
Por:
Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, Foell D, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Hilario MO, Oliveira S, Yeung RS, Rosenberg AM, Wedderburn LR, Anton-Lopez J, Haas JP, Rosen-Wolff A, Minden K, Tenbrock K, Demirkaya E, Cobb J, Baskin E, Signa S, Shuldiner E, Duerr RH, Achkar JP, Kamboh MI, Kaufman KM, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A, British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, In, Langefeld CD, Thompson S, Zeggini E, Kastner DL, Woo P and Thomson W
Publicada:
1 may 2017
Ahead of Print:
7 dic 2016
Resumen:
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.
Filiaciones:
Ombrello MJ:
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
Arthur VL:
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
Remmers EF:
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA
Hinks A:
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, Manchester, UK
Tachmazidou I:
Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, UK
Grom AA:
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Foell D:
Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany
Martini A:
Department of Pediatrics, University of Genova, Genoa, Italy
Pediatrics II Unit, Giannina Gaslini Institute, Genoa, Italy
Gattorno M:
Pediatrics II Unit, Giannina Gaslini Institute, Genoa, Italy
Özen S:
Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
Prahalad S:
Departments of Pediatrics and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
Children's Healthcare of Atlanta, Atlanta, Georgia, USA
Zeft AS:
Department of Pediatrics, Cleveland Clinic, Cleveland, Ohio, USA
Bohnsack JF:
Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
Ilowite NT:
Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA
Mellins ED:
Department of Pediatrics, Stanford University, Stanford, California, USA
Russo R:
Service of Immunology and Rheumatology, Hospital de Pediatría Garrahan, Buenos Aires, Argentina
Len C:
Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil
Hilario MO:
Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil
Oliveira S:
Universidade Federal de Rio de Janeiro, Rio de Janeiro, Brazil
Yeung RS:
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
Rosenberg AM:
Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada
Wedderburn LR:
Institute of Child Health, University College London, London, UK
Center of Paediatric and Adolescent Rheumatology, University College London, London, UK
Anton-Lopez J:
Pediatric Rheumatology Unit, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain
Haas JP:
German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany
Rosen-Wolff A:
University Hospital Cal Gustav Carus, Dresden, Germany
Minden K:
Department of Rheumatology and Clinical Immunology, Charité -University Medicine, Berlin, Germany
Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany
Tenbrock K:
Department of Pediatrics, RWTH Aachen University, Aachen, Germany
Demirkaya E:
Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
Cobb J:
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
Baskin E:
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
Signa S:
Department of Pediatrics, University of Genova, Genoa, Italy
Shuldiner E:
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
Duerr RH:
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Achkar JP:
Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA
Kamboh MI:
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Kaufman KM:
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Kottyan LC:
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Pinto D:
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Scherer SW:
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
Alarcón-Riquelme ME:
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
Docampo E:
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
Estivill X:
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
Gül A:
Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
Langefeld CD:
Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
Thompson S:
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Zeggini E:
Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, UK
Kastner DL:
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA
Woo P:
Center of Paediatric and Adolescent Rheumatology, University College London, London, UK
Thomson W:
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
Open Access
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