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An Amino Acid Motif In HLA-DRB1 Distinguishes Patients With Uveitis In Juvenile Idiopathic Arthritis
P.C.E. Hissink Muller,
A.I. Den Hollander,
M.A.J. van Rossum,
ICON-JIA study group,
R. ten Cate,
J.H. de Boer,
Sara L Pulit,
Posted 22 May 2017
bioRxiv DOI: 10.1101/140954
Posted 22 May 2017
Uveitis is a visually-debilitating disorder that affects up to 30% of children with juvenile idiopathic arthritis (JIA). To identify genetic susceptibility loci for uveitis in JIA, we conducted a genome-wide association study comparing 192 JIA-associated uveitis cases with 330 JIA individuals without uveitis. Two cohorts of JIA patients underwent genotyping and quality control. We used an HLA-specific imputation panel to impute HLA-specific amino acids and HLA types, and identified the amino acid serine at position 11 (serine-11) in HLA-DRB1 as associated to increased risk of uveitis (OR = 2.60, p = 5.43 x 10-10). The signal at serine-11 was female-specific (interaction of sex and serine-11, p = 0.0096). Serine-11 resides in the YST-motif (positions 10-12) in the peptide binding groove of HLA-DRB1. Quantitative binding affinity predictions revealed peptide-binding preferences that distinguish HLA-DRB1 allotypes with the YST-motif. Our findings highlight a genetically distinct, sexually-dimorphic feature of JIA-associated uveitis.
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