An amino acid motif in HLA-DRß1 distinguishes patients with uveitis in juvenile idiopathic arthritis

A.J.W. Haasnoot; M.W. Schilham; S.S.M. Kamphuis; P.C.E. Hissink Muller; A. Heiligenhaus; D. Foell; R.A. Ophoff; T.R.D.J. Radstake; A.I. Den Hollander; T.H.C.M. Reinards; S. Hiddingh; N. Schalij-Delfos; E.P.A.H. Hoppenreijs; M.A.J. van Rossum; C. Wouters; R.K. Saurenmann; N. Wulffraat; R. ten Cate; J.H. de Boer; S.L. Pulit; J.J.W. Kuiper

Here, we performed genotyping in 192 JIA-associated uveitis cases and 330 JIA patients without uveitis for at least 4 years, with the aim of identifying those genetic variants that segregate more commonly in JIA patients with uveitis compared to those without uveitis. All samples analysed here fall into the following International League of Associations for Rheumatology (ILAR) categories: (i) oligoarticular extended, (ii) oligoarticular persistent, and (iii) RF-negative polyarticular JIA. We analyzed the collective JIA-uveitis categories as one group to increase power, because these common categories of JIA are all particularly prone to uveitis and have recently been shown to be genetically highly similar in HLA associations. 20 To identify risk variants in a high-density set of polymorphisms, we performed two sets of imputation: one using a sequencing-based reference panel, to scan for risk-increasing alleles genome-wide; and a second, with an MHC-specific reference panel, to identify additional SNPs, amino acids, and HLA types that confer risk to disease. We identified serine (S) at position 11 in HLA-DRB1 as highly associated to increased risk of uveitis (odds ratio (OR) = 2.60 [95% CI: 1.92 -3.52], p = 5.46 x 10 -10 ). Sex-specific analysis revealed that the association at serine-11 in HLA-DRB1 was specific to females only (p females = 7.61 x 10 -10 , p males = 0.18). Quantitative prediction of peptide binding revealed that the presence of serine-11, which is located in the peptide-binding groove, affects overall peptide-binding preferences of common HLA-DRB1 allotypes.