Identification of an Amino Acid Motif in HLA-DRβ1 That Distinguishes Uveitis in Patients With Juvenile Idiopathic Arthritis

Arthritis Rheumatol. 2018 Jul;70(7):1155-1165. doi: 10.1002/art.40484. Epub 2018 May 29.


Objective: Uveitis is a visually debilitating disorder that affects up to 30% of children with the most common forms of juvenile idiopathic arthritis (JIA). The disease mechanisms predisposing only a subgroup of children to uveitis are unknown. This study was undertaken to identify genetic susceptibility loci for uveitis in JIA, using a genome-wide association study in 522 children with JIA.

Methods: Two cohorts of JIA patients with ophthalmologic follow-up data were genotyped. Data were then imputed using a genome-wide imputation reference panel, and an HLA-specific reference panel was used for imputing amino acids and HLA types in the major histocompatibility complex (MHC). After imputation, genome-wide and MHC-specific analyses were performed, and a reverse immunology approach was utilized to model antigen presentation at 13 common HLA-DRβ1 alleles.

Results: Presence of the amino acid serine at position 11 (serine 11) in HLA-DRβ1 was associated with an increased risk of uveitis in JIA patients (odds ratio [OR] 2.60, P = 5.43 × 10-10 ) and was specific to girls (Pfemales = 7.61 × 10-10 versus Pmales = 0.18). Serine 11 resides in the YST motif in the peptide-binding groove of HLA-DRβ1; all 3 amino acids in this motif are in perfect linkage disequilibrium and show identical association with disease. Quantitative prediction of binding affinity revealed that HLA-DRβ1 alleles with the YST motif could be distinguished on the basis of discernable peptide-binding preferences.

Conclusion: These findings highlight a genetically distinct, sexually dimorphic feature of JIA with uveitis as compared to JIA without uveitis. The association could be indicative of the potential involvement of antigen presentation by HLA-DRβ1 in the development of uveitis in JIA. The results of this study may advance our progress toward improved treatments for, and possible prevention of, the sight-threatening complications of uveitis in children with JIA.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Amino Acid Motifs / genetics*
  • Arthritis, Juvenile / genetics*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • HLA-DRB1 Chains / genetics*
  • Humans
  • Male
  • Odds Ratio
  • Uveitis / genetics*


  • HLA-DRB1 Chains