An amino acid motif in HLA-DR beta 1 distinguishes patients with uveitis in juvenile idiopathic arthritis

Purpose : 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. To identify genetic susceptibility loci for uveitis in JIA, we conducted a genome-wide association study totalling 522 JIA cases.

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

Results : We identified the amino acid serine at position 11 (serine-11) in HLA-DRβ1 as associated to increased risk of uveitis (OR = 2.60, p = 5.43 x 10-10) and specific to females (pfemales = 7.61 x 10-10, pmales = 0.18). Serine-11 resides in the YST-motif in the peptide binding groove of HLA-DRβ1; all three amino acids are in perfect linkage disequilibrium and show identical association to disease. Quantitative prediction of binding affinity revealed that discernable peptide-binding preferences distinguish HLA-DRβ1 alleles with the YST-motif.

Conclusions : Our findings highlight a genetically distinct, sexually-dimorphic feature of JIA-uveitis compared to non-uveitis JIA. The association indicates the potential involvement for antigen presentation by HLA-DRβ1 in the development of uveitis in JIA. This work will advance our progress towards treating and preventing sight-threatening complications of uveitis in children with JIA.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.