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  • Title: Identification of an Amino Acid Motif in HLA-DRβ1 That Distinguishes Uveitis in Patients With Juvenile Idiopathic Arthritis.
    Author: Haasnoot AJW, Schilham MW, Kamphuis S, Hissink Muller PCE, Heiligenhaus A, Foell D, Minden K, Ophoff RA, Radstake TRDJ, Den Hollander AI, Reinards THCM, Hiddingh S, Schalij-Delfos NE, Hoppenreijs EPAH, van Rossum MAJ, Wouters C, Saurenmann RK, van den Berg JM, Wulffraat NM, ICON-JIA Study Group, Ten Cate R, de Boer JH, Pulit SL, Kuiper JJW.
    Journal: Arthritis Rheumatol; 2018 Jul; 70(7):1155-1165. PubMed ID: 29513936.
    Abstract:
    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.
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