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Identification of an Amino Acid Motif in HLA – DR β1 That Distinguishes Uveitis in Patients With Juvenile Idiopathic Arthritis
Author(s) -
Haasnoot AnneMieke J. W.,
Schilham Marco W.,
Kamphuis Sylvia,
Hissink Muller Petra C. E.,
Heiligenhaus Arnd,
Foell Dirk,
Minden Kirsten,
Ophoff Roel A.,
Radstake Timothy R. D. J.,
Den Hollander Anneke I.,
Reinards Tjitske H. C. M.,
Hiddingh Sanne,
SchalijDelfos Nicoline E.,
Hoppenreijs Esther P. A. H.,
Rossum Marion A. J.,
Wouters Carine,
Saurenmann Rotraud K.,
Berg J. Merlijn,
Wulffraat Nico M.,
Cate Rebecca,
Boer Joke H.,
Pulit Sara L.,
Kuiper Jonas J. W.
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40484
Subject(s) - uveitis , human leukocyte antigen , arthritis , linkage disequilibrium , imputation (statistics) , immunology , major histocompatibility complex , genome wide association study , genetics , allele , biology , medicine , haplotype , single nucleotide polymorphism , genotype , antigen , gene , machine learning , missing data , computer science
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 .