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Extended report
CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis
  1. T H C M Reinards1,
  2. H M Albers1,
  3. D M C Brinkman2,
  4. S S M Kamphuis3,
  5. M A J van Rossum4,
  6. H J Girschick5,
  7. C Wouters6,
  8. E P A H Hoppenreijs7,
  9. R K Saurenmann8,
  10. A Hinks9,
  11. J A Ellis10,11,
  12. E Bakker12,
  13. W Verduijn13,
  14. P Slagboom14,
  15. T W J Huizinga15,
  16. R E M Toes15,
  17. J J Houwing-Duistermaat16,
  18. R ten Cate1,
  19. M W Schilham17
  1. 1Department of Pediatrics/Pediatric Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Pediatrics/Pediatric Rheumatology, Rijnland Hospital, Leiderdorp, The Netherlands
  3. 3Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
  4. 4Department of Pediatrics/Pediatric Rheumatology, Academic Medical Centre/Emma Children's Hospital and Reade (Jan van Breemen location), Amsterdam, The Netherlands
  5. 5Vivantes Children's Hospital, Berlin-Friedrichshain, Germany
  6. 6University Hospital Gasthuisberg, Leuven, Belgium
  7. 7Department of Pediatrics/Pediatric Rheumatology, St Maartenskliniek and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  8. 8Zürich University Children's Hospital, Zürich, Switzerland
  9. 9Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
  10. 10Department of Pediatrics, The University of Melbourne, Melbourne, Australia
  11. 11Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia
  12. 12Centre for Human and Clinical Genetics/Laboratory for Diagnostic Genome Analysis, Leiden University Medical Center, Leiden, The Netherlands
  13. 13Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, The Netherlands
  14. 14Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  15. 15Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  16. 16Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
  17. 17Department of Pediatrics/Laboratory for Immunology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Marco W Schilham, Department of Pediatrics, P3-P, Leiden University Medical Center, PO Box 9600, 2300RC, Leiden, The Netherlands; M.W.Schilham{at}


Objectives Juvenile idiopathic arthritis (JIA) is considered a complex genetic autoimmune disease. We investigated the association of genetic variants previously implicated in JIA, autoimmunity and/or immunoregulation, with susceptibility to JIA.

Methods A genetic association study was performed in 639 JIA patients and 1613 healthy controls of northwest European descent. Ninety-three single nucleotide polymorphisms (SNP) were genotyped in a candidate gene approach. Results of the entire JIA patient group (all subtypes) were compared with results obtained, alternatively, with a clinically homogeneous patient group including only oligoarticular and rheumatoid factor (RF) negative polyarticular JIA patients (n=493). Meta-analyses were performed for all SNPs that have been typed in other Caucasian JIA cohorts before.

Results SNPs in or near PTPN22, VTCN1, the IL2-IL21 region, ANKRD55 and TNFA were confirmed to be associated with JIA (p<0.05), strengthening the evidence for involvement of these genes in JIA. In the majority of these replicated SNPs, effect sizes were larger when analysing a homogeneous patient cohort than when analysing all subtypes. We identified two novel associations with oligoarticular and RF-negative polyarticular JIA: CD226 rs763361 (OR 1.30, 95% CI 1.12 to 1.51, p=0.0006) and CD28 rs1980422 (OR 1.29, 95% CI 1.07 to 1.55, p=0.008). Meta-analyses including reported studies confirmed the association of both SNPs with susceptibility to JIA (OR 1.16, p=0.001 and OR 1.18, p=0.001, for rs763361 and rs1980422, respectively).

Conclusions The CD226 gene has been identified as novel association with JIA, and a SNP near CD28 as a suggestive association. Both genes are probable candidate risk factors, since they are involved in costimulation of T cells.

  • Juvenile Idiopathic Arthritis
  • Gene Polymorphism
  • T Cells
  • Autoimmune Diseases

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