July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
An amino acid motif in HLA-DRβ1 distinguishes patients with uveitis in juvenile idiopathic arthritis
Author Affiliations & Notes
  • Anne-Mieke Haasnoot
    Ophthalmology and Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands
  • M.W. Schilham
    Paediatric Rheumatology, UMC Leiden, Leiden, Netherlands
  • S Kamphuis
    Pediatric Rheumatology, Erasmus University Medical Center, Rotterdam, Netherlands
  • P Hissink-muller
    Paediatric Rheumatology, UMC Leiden, Leiden, Netherlands
  • Arnd Heiligenhaus
    Ophthalmology, Ophtha Lab at St. Franziskus-Hospital, Muenster, Germany
  • D Foell
    Pediatric Rheumatology and Immunology, University of Muenster, Muenster, Germany
  • K Minden
    Rheumatology and Clinical Immunology, German Rheumatism Research Center Berlin-Leibniz Institute, and Charité University Medicine, Berlin, Germany
  • R.A. Ophoff
    Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
    Human Genetics and Neuroscience and Human Behavior, University of California, California, California, United States
  • Timothy Radstake
    Rheumatology and Clinical Immunology, UMC Utrecht, Utrecht, Netherlands
  • Anneke I Den Hollander
    Ophthalmology and Human Genetics, Donders Institute of Brain, Cognition, and Behaviour, Donders Institute of Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
  • T Reinards
    Paediatric Rheumatology, UMC Leiden, Leiden, Netherlands
  • Sanne Hiddingh
    Ophthalmology and Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands
  • N. Schalij-Delofs
    Ophthalmology, Leiden University Medical Center, Leiden, Netherlands
  • Joke de Boer
    Ophthalmology and Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands
  • S Pulit
    Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
  • Jonas Kuiper
    Ophthalmology and Laboratory of Translational Immunology, UMC Utrecht, Utrecht, Netherlands
  • Footnotes
    Commercial Relationships   Anne-Mieke Haasnoot, None; M.W. Schilham, None; S Kamphuis, None; P Hissink-muller, None; Arnd Heiligenhaus, None; D Foell, None; K Minden, None; R.A. Ophoff, None; Timothy Radstake, None; Anneke Den Hollander, None; T Reinards, None; Sanne Hiddingh, None; N. Schalij-Delofs, None; Joke de Boer, None; S Pulit, None; Jonas Kuiper, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3492. doi:
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      Anne-Mieke Haasnoot, M.W. Schilham, S Kamphuis, P Hissink-muller, Arnd Heiligenhaus, D Foell, K Minden, R.A. Ophoff, Timothy Radstake, Anneke I Den Hollander, T Reinards, Sanne Hiddingh, N. Schalij-Delofs, Joke de Boer, S Pulit, Jonas Kuiper; An amino acid motif in HLA-DRβ1 distinguishes patients with uveitis in juvenile idiopathic arthritis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3492.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

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.

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