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  • Arthritis Curehow to Arthritis Cure for 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 for 1 last update 2020/05/28 OmbrelloMichael J Ombrello1,
  2. Arthritis Curehow to Arthritis Cure for Victoria L Arthur1,
  3. Elaine F Remmers2,
  4. Anne Hinks3,
  5. Arthritis Curehow to Arthritis Cure for Ioanna Tachmazidou4,
  6. Alexei A Grom5,6,
  7. Dirk Foell7,
  8. Alberto Martini8,9,
  9. Marco Gattorno9,
  10. Seza Özen10,
  11. Sampath Prahalad11Arthritis Curehow to Arthritis Cure for ,12,
  12. Arthritis Curehow to Arthritis Cure for Andrew S Zeft13,
  13. John F Bohnsack14,
  14. Norman T Ilowite15,
  15. Elizabeth D Mellins16,
  16. Arthritis Curehow to Arthritis Cure for Ricardo Russo17,
  17. Claudio Len18,
  18. Maria Odete E Hilario18,
  19. Arthritis Curehow to Arthritis Cure for Sheila Oliveira19,
  20. Rae S M Yeung20,21,22,
  21. Alan M Rosenberg23,
  22. Lucy R Wedderburn24 for 1 last update 2020/05/28 ,,25,
  23. Jordi Anton26,
  24. Johannes-Peter Haas27,
  25. Angela Rosen-Wolff28,
  26. Kirsten Minden29,30,
  27. Klaus Tenbrock31,
  28. Erkan Demirkaya10,
  29. Joanna Cobb3Arthritis Curehow to Arthritis Cure for ,32,
  30. Elizabeth Baskin1,
  31. Sara for 1 last update 2020/05/28 SignaSara Signa8,
  32. Emily Shuldiner1,
  33. Richard H for 1 last update 2020/05/28 DuerrRichard H Duerr33,34,
  34. Jean-Paul Achkar35,36,
  35. M Ilyas Kamboh34,
  36. Kenneth M Kaufman5,6,
  37. http://orcid.org/0000-0003-3979-2220Leah C Kottyan5,6,
  38. Dalila Pinto37,
  39. Stephen W Scherer38,
  40. Marta E Alarcón-Riquelme39,40,
  41. Elisa Docampo41 the 1 last update 2020/05/28 ,,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 Thompson5Arthritis Curehow to Arthritis Cure for ,6,
  47. Eleftheria Zeggini4,
  48. Daniel L Kastner2,
  49. Patricia for 1 last update 2020/05/28 WooPatricia Woo25,
  50. Wendy for 1 last update 2020/05/28 ThomsonWendy 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 the 1 last update 2020/05/28 Services, Bethesda, MarylandUS 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, Arthritis Curehow to Arthritis Cure for Manchester, UK
  4. 4Human Genetics, The Wellcome Trust Sanger Institute, Hinxton, UK
  5. 5Arthritis Curehow to Arthritis Cure for Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  6. 6Cincinnati Children''s Healthcare of Atlanta, Atlanta, Georgia, USA
  7. 13Department of Pediatrics, Cleveland Clinic, Cleveland, Ohio, USA
  8. 14Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
  9. 15Department of Pediatrics, Albert Einstein College of Medicine and Children''s Disease
  10. Gene Polymorphism
  11. 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/

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    • Juvenile Idiopathic Arthritis
    • Adult Onset Still''s disease) is characterised by prominent systemic inflammation and has a rare adult-onset counterpart;3 and undifferentiated arthritis includes arthritis that does not fit into any single category.1 ,2

      sJIA is among the most severe childhood inflammatory diseases. First described by Sir George Frederic Still over a century ago, sJIA is marked by arthritis and systemic inflammation with quotidian fever, evanescent salmon pink skin rash, lymphadenopathy, hepatosplenomegaly and serositis.2 ,4 It is frequently complicated by macrophage activation syndrome, a potentially lethal form of hemophagocytic lymphohistiocytosis.5 Although sJIA only constitutes approximately 10% of JIA in populations of European descent,1 for 1 last update 2020/05/28 ,,5 its disproportionately large share of the morbidity and mortality observed in JIA6 underscores the importance of understanding and targeting its root causes.

      The unique clinical characteristics of sJIA suggest that it is distinct from other forms of JIA, leading to the contention by some that sJIA should be separated from other forms of JIA and labelled as an autoinflammatory disease.7 This has been challenged by identification of autoantibodies in some patients with sJIA.8 Furthermore, while the systemic inflammatory features of sJIA seem to distinguish it from other forms of JIA, most children with sJIA eventually shed these features, leaving up to half of children with a persistent form of arthritis that is similar to the oligoarticular and polyarticular forms of JIA.5 ,9 Finally, significant differential effects of anticytokine agents have been observed between sJIA and other forms of JIA.10 However, due to the highly variable therapeutic responses to each agent in sJIA, this has not concretely advanced our understanding of how sJIA mechanistically relates to other forms of JIA.

      One approach to evaluate the similarity of diseases is to examine shared pathophysiology through statistical comparisons of for 1 last update 2020/05/28 disease-specific genetic association data.11 For example, studies of inflammatory bowel disease and spondyloarthritis have identified shared genetic risk factors, providing rationale for similar treatment choices.11 In JIA, the majority of genetic and genomic investigations have focused on the combination of the most common subtypes, oligoJIA and RF–polyJIA (henceforth referred to in this manuscript as polygoJIA),12 ,13 but until recently,14 because of insufficient numbers of patients with sJIA, there have been only underpowered genetic studies and no genome-wide studies of sJIA. Comparisons of the genomic underpinnings of sJIA relative to other forms of JIA have therefore also been lacking.One approach to evaluate the similarity of diseases is to examine shared pathophysiology through statistical comparisons of disease-specific genetic association data.11 For example, studies of inflammatory bowel disease and spondyloarthritis have identified shared genetic risk factors, providing rationale for similar treatment choices.11 In JIA, the majority of genetic and genomic investigations have focused on the combination of the most common subtypes, oligoJIA and RF–polyJIA (henceforth referred to in this manuscript as polygoJIA),12 ,13 but until recently,14 because of insufficient numbers of patients with sJIA, there have been only underpowered genetic studies and no genome-wide studies of sJIA. Comparisons of the genomic underpinnings of sJIA relative to other forms of JIA have therefore also been lacking.

      To gain insight into the pathogenesis of sJIA, we established the International Childhood Arthritis Genetics (INCHARGE) consortium. Together, we gathered the largest sJIA study population ever assembled, which included 982 children from nine countries on three continents. Using this collection, we performed the first genome-wide association study (GWAS) of sJIA. We recently reported the results of our intensive examination of the major histocompatibility complex (MHC) locus in this study population, which identified the class II human leucocyte antigen (HLA) region as a strong sJIA susceptibility locus.14 Here, we report the findings of the GWAS, beyond the MHC locus. Using the GWAS results, we have performed the first direct comparison of the genetic architecture of sJIA with those of the most common forms of JIA.

    Methods

    Study design and participants

    Peripheral blood specimens were collected from children diagnosed with sJIA according to the International League of Associations for Rheumatology (ILAR) criteria2 by paediatric rheumatologists at participating medical centres in nine countries (see online supplementary text and figure S1). Blood samples were also obtained from geographically matched control subjects. In addition, single nucleotide polymorphism (SNP) genotype data from geographically matched control populations were used, when available. The INCHARGE project was granted institutional review board (IRB) approval by the University of Manchester. Subjects were enrolled in accordance with all local ethics regulations, with the approval of local IRBs at each contributing medical centre, and with informed parental consent.

    supplementary data

    Arthritis Curehow to Arthritis Cure for [annrheumdis-2016-210324supp_appendix.pdf]

    Arthritis Curehow to Arthritis Cure for Genotyping, quality control and imputation

    Arthritis Curehow to Arthritis Cure for Genomic DNA was extracted from peripheral blood samples. Samples were genotyped at the National Human Genome Research Institute (Bethesda, Maryland, USA) using Human Omni1M arrays (Illumina) in accordance with the manufacturer''s clinical history, etiology, and pathology. Lancet 1896;147:11205. doi:10.1016/S0140-6736(01)61263-7

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    3. Arthritis Curehow to Arthritis Cure for D''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).

    4. 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.

    5. Ethics approval University of Manchester.

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

    7. Arthritis Curehow to Arthritis Cure for 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.

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    Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ 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/

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