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

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

Author information

1
University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
2
Leiden University Medical Center, Leiden, The Netherlands.
3
Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands.
4
St. Franziskus-Hospital, Muenster, Germany, and University of Duisburg, Essen, Germany.
5
University of Muenster, Muenster, Germany.
6
German Rheumatism Research Center Berlin-Leibniz Institute and Charite University Medicine, Berlin, Germany.
7
University Medical Center Utrecht, Utrecht, The Netherlands, and University of California, Los Angeles.
8
Radboud University Medical Center, Nijmegen, The Netherlands.
9
Emma Children's Hospital AMC and Amsterdam Rheumatology and Immunology Center Reade, Amsterdam, The Netherlands.
10
University of Leuven and University Hospitals Leuven, Leuven, Belgium.
11
University Children's Hospital, Zurich, Switzerland.
12
Emma Children's Hospital AMC and University of Amsterdam, Amsterdam, The Netherlands.
13
University Medical Center Utrecht, Utrecht, The Netherlands, and Oxford University, Oxford, UK.

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.

PMID:
29513936
DOI:
10.1002/art.40484
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