title: Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope.
abstract: OBJECTIVE
  Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE.
  
  
  METHODS
  High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S(2) , S(3P) , or L alleles, based on amino acid sequences in position 70-74 of the DRβ1 chain, as proposed by Tezenas du Montcel et al.
  
  
  RESULTS
  We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76% of patients carried 1 or 2 SE alleles compared with 46% of control subjects; OR 3.81, 95% CI 2.4-6.0, P < 1 × 10(-7) ). We also observed associations between individual SE alleles (HLA-DRB1*0101, *0401, *0404, *0405, *0408, and *1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S(2) /S(3P)  (OR 22.3, 95% CI 9.9-50.5, P < 0.0001).
  
  
  CONCLUSIONS
  We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S(2)  and S(3P)  risk alleles suggests that children with DRβ1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA.
authors.affiliation: Pediatrics and Human Genetics, Emory University, Atlanta, GA 30322, USA. sprahal@emory.edu
authors.forename: Sampath
authors.initials: S
authors.lastname: Prahalad
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.forename: Yunxuan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Traci
authors.initials: T
authors.lastname: Leong
authors.forename: Jennifer
authors.initials: J
authors.lastname: Prozonic
authors.forename: Milton R
authors.initials: MR
authors.lastname: Brown
authors.forename: Lori A
authors.initials: LA
authors.lastname: Ponder
authors.forename: Sheila T
authors.initials: ST
authors.lastname: Angeles-Han
authors.forename: Larry B
authors.initials: LB
authors.lastname: Vogler
authors.forename: Christine
authors.initials: C
authors.lastname: Kennedy
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wallace
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
authors.forename: Marilynn
authors.initials: M
authors.lastname: Punaro
authors.forename: Ann
authors.initials: A
authors.lastname: Reed
authors.forename: Jane L
authors.initials: JL
authors.lastname: Park
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Zeft
authors.forename: John F
authors.initials: JF
authors.lastname: Bohnsack
authors.forename: David N
authors.initials: DN
authors.lastname: Glass
mesh_terms: D017668:Age of Onset; D000483:Alleles; D001171:Arthritis, Juvenile / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D002648:Child; D020022:Genetic Predisposition to Disease; D005845:Georgia / Q000453:epidemiology; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics*; D012307:Risk Factors
chemical_list: D059811:HLA-DRB1 Chains; D016056:Immunodominant Epitopes