title: Susceptibility to childhood-onset rheumatoid arthritis: investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci.
abstract: OBJECTIVE
  Children with childhood-onset rheumatoid arthritis (RA) include those with rheumatoid factor or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. To test the hypothesis that adult-onset RA-associated variants are also associated with childhood-onset RA, we investigated RA-associated variants at 5 loci in a cohort of patients with childhood-onset RA. We also assessed the cumulative association of these variants in susceptibility to childhood-onset RA using a weighted genetic risk score (wGRS).
  
  
  METHODS
  A total of 155 children with childhood-onset RA and 684 healthy controls were genotyped for 5 variants in the PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with childhood-onset RA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios (ORs) for the alleles investigated, and used logistic regression to test the wGRS for association with childhood-onset RA.
  
  
  RESULTS
  Childhood-onset RA was associated with TNFAIP3 rs10499194 (OR 0.60 [95% confidence interval 0.44-0.83]), PTPN22 rs2476601 (OR 1.61 [95% confidence interval 1.11-2.31]), and STAT4 rs7574865 (OR 1.41 [95% confidence interval 1.06-1.87]) variants. The wGRS was significantly different between cases and controls (P < 2 × 10(-16) ). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to baseline (individuals in the first quintile). Higher wGRS was associated with increased risk of childhood-onset RA, especially among males.
  
  
  CONCLUSIONS
  The magnitude and direction of the association between TNFAIP3, STAT4, and PTPN22 variants and childhood-onset RA are similar to those observed in RA, suggesting that adult-onset RA and childhood-onset RA share common genetic risk factors. Using a wGRS, we have demonstrated the cumulative association of RA-associated variants with susceptibility to childhood-onset RA.
authors: Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors: Sampath
authors: S
authors: Prahalad
authors: Karen N
authors: KN
authors: Conneely
authors: Yunxuan
authors: Y
authors: Jiang
authors: Marc
authors: M
authors: Sudman
authors: Carol A
authors: CA
authors: Wallace
authors: Milton R
authors: MR
authors: Brown
authors: Lori A
authors: LA
authors: Ponder
authors: Mina
authors: M
authors: Rohani-Pichavant
authors: Michael E
authors: ME
authors: Zwick
authors: David J
authors: DJ
authors: Cutler
authors: Sheila T
authors: ST
authors: Angeles-Han
authors: Larry B
authors: LB
authors: Vogler
authors: Christine
authors: C
authors: Kennedy
authors: Kelly
authors: K
authors: Rouster-Stevens
authors: Carol A
authors: CA
authors: Wise
authors: Marilynn
authors: M
authors: Punaro
authors: Ann M
authors: AM
authors: Reed
authors: Elizabeth D
authors: ED
authors: Mellins
authors: John F
authors: JF
authors: Bohnsack
authors: David N
authors: DN
authors: Glass
authors: Susan D
authors: SD
authors: Thompson
mesh_terms: D000328:Adult; D000367:Age Factors; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002648:Child; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D018570:Risk Assessment