title: CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis.
abstract: OBJECTIVE
  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.
authors: Department of Pediatrics/Pediatric Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: T H C M
authors: TH
authors: Reinards
authors: Department of Pediatrics/Pediatric Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: H M
authors: HM
authors: Albers
authors: Department of Pediatrics/Pediatric Rheumatology, Rijnland Hospital, Leiderdorp, The Netherlands.
authors: D M C
authors: DM
authors: Brinkman
authors: Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: S S M
authors: SS
authors: Kamphuis
authors: Department of Pediatrics/Pediatric Rheumatology, Academic Medical Centre/Emma Children's Hospital and Reade (Jan van Breemen location), Amsterdam, The Netherlands.
authors: M A J
authors: MA
authors: van Rossum
authors: Vivantes Children's Hospital, Berlin-Friedrichshain, Germany.
authors: H J
authors: HJ
authors: Girschick
authors: University Hospital Gasthuisberg, Leuven, Belgium.
authors: C
authors: C
authors: Wouters
authors: Department of Pediatrics/Pediatric Rheumatology, St Maartenskliniek and Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: E P A H
authors: EP
authors: Hoppenreijs
authors: Zürich University Children's Hospital, Zürich, Switzerland.
authors: R K
authors: RK
authors: Saurenmann
authors: Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
authors: A
authors: A
authors: Hinks
authors: Department of Pediatrics, The University of Melbourne, Melbourne, Australia Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.
authors: J A
authors: JA
authors: Ellis
authors: Centre for Human and Clinical Genetics/Laboratory for Diagnostic Genome Analysis, Leiden University Medical Center, Leiden, The Netherlands.
authors: E
authors: E
authors: Bakker
authors: Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors: W
authors: W
authors: Verduijn
authors: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: P
authors: P
authors: Slagboom
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: T W J
authors: TW
authors: Huizinga
authors: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: R E M
authors: RE
authors: Toes
authors: Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
authors: J J
authors: JJ
authors: Houwing-Duistermaat
authors: Department of Pediatrics/Pediatric Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: R
authors: R
authors: ten Cate
authors: Department of Pediatrics/Laboratory for Immunology, Leiden University Medical Center, Leiden, The Netherlands.
authors: M W
authors: MW
authors: Schilham
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000378:metabolism; D001171:Arthritis, Juvenile / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D004247:DNA
keywords: Autoimmune Diseases; Gene Polymorphism; Juvenile Idiopathic Arthritis; T Cells