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

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Basic and translational research
Extended report
Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications
  1. Michael J Ombrello1,
  2. Victoria L Arthur1,
  3. Elaine F Remmers2,
  4. Anne Hinks3,
  5. Ioanna Tachmazidou4,
  6. Alexei A Grom5,6,
  7. Dirk Foell7,
  8. Alberto Martini8,9,
  9. Marco Gattorno9,
  10. Seza Özen10,
  11. Sampath Prahalad11,12,
  12. Andrew S Zeft13,
  13. John F Bohnsack14,
  14. Norman T Ilowite15,
  15. Elizabeth D Mellins16,
  16. Ricardo Russo17,
  17. Claudio Len18,
  18. Maria Odete E Hilario18,
  19. Sheila Oliveira19,
  20. Rae S M Yeung20,21,22,
  21. Alan M Rosenberg23,
  22. Lucy R Wedderburn24,25,
  23. Jordi Anton26,
  24. Johannes-Peter Haas27,
  25. Angela Rosen-Wolff28,
  26. Kirsten Minden29,30,
  27. Klaus Tenbrock31,
  28. Erkan Demirkaya10,
  29. Joanna Cobb3,32,
  30. Elizabeth Baskin1,
  31. Sara Signa8,
  32. Emily Shuldiner1,
  33. Richard H Duerr33,34,
  34. Jean-Paul Achkar35,36,
  35. M Ilyas Kamboh34,
  36. Kenneth M Kaufman5,6,
  37. Leah C Kottyan5,6,
  38. Dalila Pinto37,
  39. Stephen W Scherer38,
  40. Marta E Alarcón-Riquelme39,40,
  41. Elisa Docampo41,42,
  42. Xavier Estivill42,43,
  43. Ahmet Gül44,
  44. British Society of Pediatric and Adolescent Rheumatology (BSPAR) Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis (ICON-JIA) Study Group, Childhood Arthritis Prospective Study (CAPS) Group, Randomized Placebo Phase Study of Rilonacept in sJIA (RAPPORT) Investigators, Sparks-Childhood Arthritis Response to Medication Study (CHARMS) Group, Biologically Based Outcome Predictors in JIA (BBOP) Group,
  45. Carl D Langefeld45,
  46. Susan Thompson5,6,
  47. Eleftheria Zeggini4,
  48. Daniel L Kastner2,
  49. Patricia Woo25,
  50. Wendy Thomson3,32
  1. 1Translational 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. 2Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA
  3. 3Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, Manchester, UK
  4. 4Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, UK
  5. 5Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  6. 6Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  7. 7Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany
  8. 8Department of Pediatrics, University of Genova, Genoa, Italy
  9. 9Pediatrics II Unit, Giannina Gaslini Institute, Genoa, Italy
  10. 10Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
  11. 11Departments of Pediatrics and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA
  12. 12Children's Healthcare of Atlanta, Atlanta, Georgia, USA
  13. 13Department of Pediatrics, Cleveland Clinic, Cleveland, Ohio, USA
  14. 14Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
  15. 15Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA
  16. 16Department of Pediatrics, Stanford University, Stanford, California, USA
  17. 17Service of Immunology and Rheumatology, Hospital de Pediatria Garrahan, Buenos Aires, Argentina
  18. 18Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, Brazil
  19. 19Universidade Federal de Rio de Janeiro, Rio de Janeiro, Brazil
  20. 20Department of Pediatrics, University of Toronto, Toronto, Canada
  21. 21Department of Immunology, University of Toronto, Toronto, Canada
  22. 22Institute of Medical Science, University of Toronto, Toronto, Canada
  23. 23Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada
  24. 24Institute of Child Health, University College London, London, UK
  25. 25Center of Paediatric and Adolescent Rheumatology, University College London, London, UK
  26. 26Pediatric Rheumatology Unit, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain
  27. 27German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany
  28. 28University Hospital Cal Gustav Carus, Dresden, Germany
  29. 29Department of Rheumatology and Clinical Immunology, Charité -University Medicine, Berlin, Germany
  30. 30Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany
  31. 31Department of Pediatrics, RWTH Aachen University, Aachen, Germany
  32. 32National 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. 33Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  34. 34Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  35. 35Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
  36. 36Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA
  37. 37Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  38. 38The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
  39. 39Center for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Government, Granada, Spain
  40. 40Unit of Chronic Inflammatory Diseases, Institute for Environmental Medicine, Karolinska Institutet, Solna, Sweden
  41. 41Interdisciplinary Cluster for Applied Genoproteomics-Université de Liège, Liège, Belgium
  42. 42Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, and Universitat Pompeu Fabra (UPF), Barcelona, Spain
  43. 43Sidra Medical and Research Centre, Doha, Qatar
  44. 44Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
  45. 45Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
  1. Correspondence to Dr Michael J Ombrello, Translational Genetics and Genomics Unit, Office of the Clinical Director, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, US Department of Health and Human Services, 10 Center Drive, 12N248A, Building 10, MSC1560, Bethesda, MD 20852, USA; Michael.Ombrello{at}nih.gov

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.

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

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/annrheumdis-2016-210324

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    Footnotes

    • Handling editor Tore K Kvien

    • Twitter Follow NIAMS/NIH/DHHS @NIH_NIAMS; Ricardo Russo @el_reumatologo; University of Manchester, Centre for Musculoskeletal Disease @UoMMskResearch

    • Collaborators Full membership of collaborating consortia are listed in the supplementary text: British Society of Pediatric and Adolescent Rheumatology Study Group, Inception Cohort of Newly Diagnosed Patients with Juvenile Idiopathic Arthritis Study Group, Childhood Arthritis Prospective Study Group, Randomized Placebo Phase Study of Rilonacept in sJIA Investigators, Sparks-Childhood Arthritis Response to Medication Study Group and Biologically Based Outcome Predictors in JIA Group.

    • Contributors All authors participated in study design; AAG, DF, AM, MG, SÖ, SP, ASZ, JFB, NTI, EDM, RR, CL, MOEH, SO, RSMY, AMR, LRW, JA, J-PH, AR-W, KM, KT, ED, BSPAR, ICON-JIA, CAPS, RAPPORT, CHARMS, BBOP, RHD, JPA, MIK, KMK, LCK, DP, SWS, MEA-R, ED, XE and AG provided samples for the study; MJO, VLA, EFR, AH, IT, EZ, PW and WT performed the research and analysis and interpreted the data; all authors drafted and/or substantively edited the manuscript and have thoroughly reviewed and approved of the content.

    • Funding This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01-AR041198 to MJO) and the National Human Genome Research Institute (Z01-HG200370 to DLK) of the National Institutes of Health (NIH). Additional funding was provided by NIH grants R01-AR059049 (AAG), R01AR061297 (EDM), R01-AR060893 (SP), P30-AR47363 and P01-AR48929 (ST), AG030653, AG041718 and AG005133 (MIK) and U01-DK062420 and R01-DK076025 (RHD); Arthritis Research UK Grant 20385 (WT); the German Federal Ministry of Education and Research (BMBF project 01ER0813) for the ‘ICON-JIA’ inception cohort (KM and DF); the Val A. Browning Charitable Foundation (JFB); the Marcus Foundation (SP); the Proyecto de Excelencia (CTS-2548) of the Andalousian Government (MA-R) and the Swedish Association Against Rheumatism (MA-R). IT and EZ were supported by the Wellcome Trust (098051). WT and JC are funded by the National Institute for Health Research Biomedical Research Unit Funding Scheme. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The CAPS study was funded by Arthritis Research UK Grant 20542. WT, AH, and JC are supported by the Manchester Academic Health Sciences Centre (MAHSC). SPARKS-CHARMS was funded by grants from SPARKS UK (08ICH09 and 12ICH08), the Medical Research Council (MR/M004600/1) and the UK National Institute for Health Research GOSH Biomedical Research Centre. The BBOP study was supported by the Canadian Institutes of Health Research and the Arthritis Society (CIHR funding reference number 82517) and the Canadian Arthritis Network (funding reference SRI-IJD-01). This research was supported in part by the Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort. The authors acknowledge the use of DNA from the UK Blood Services collection of Common Controls (UKBS-CC collection), which is funded by Wellcome Trust grant 076113/C/04/Z and by the USA NIH research programme grant to the National Health Service Blood and Transplant (RP-PG-0310-1002). The authors acknowledge the use of DNA from the British 1958 Birth Cohort collection, which is funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. This study used the computational resources of the Biowulf system at the NIH, Bethesda, MD (http://biowulf.nih.gov).

    • Competing interests AAG: consulting fees and honoraria from Novimmune, Novartis, Roche. AM: consulting fees and honoraria from Abbvie, Boehringer, Celgene, CrescendoBio, Janssen, Meddimune, Novaris, NovoNordisk, Pfizer, Sanofi Aventis, Vertex and Servier, contributions have been received by G. Gaslini Hospital and the PRINTO network by BMS, GlaxoSmithKline, Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Abbot, Francesco Angelini S.P.A., Sobi, and Merck Serono. MG: consulting and speaker fees from SOBI and Novartis, unrestricted grants to Eurofever from SOBI and Novartis. SP: consulting fees from Novartis. EDM: consulting fees from Novartis. LRW: speaker fees from Pfizer.

    • Ethics approval University of Manchester.

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

    • Data sharing statement The quality control processed directly genotyped SNP genotype data from sJIA cases genotyped for this study will be deposited into the National Institutes of Health’s Database of Genotypes and Phenotypes, where allowable by the Ethics and consent documents. The future use of these data will be dictated by the terms of Ethics and consent documents and the institutional certifications provided by the collaborating centres.