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

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 – DR β1 alleles. Results Presence of the amino acid serine at position 11 (serine 11) in HLA – DR β1 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 ( P females = 7.61 × 10 −10 versus P males = 0.18). Serine 11 resides in the YST motif in the peptide‐binding groove of HLA – DR β1; 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 – DR β1 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 – DR β1 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 .