New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

Abstract

Background Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci. Methods 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with noninfectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method. Results The highest peak belonged to the HLA region.

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

“…Regardless, the strongest associations for Birdshot include the rs2287987-rs10044354 haplotype and HLA-A29, a triad of loci that encode functionally tightly related proteins of the class I antigen presentation pathway and warrants further investigation into antigen presentation in human uveitis. Whether ERAP1 and ERAP2 contribute to disease by direct interaction in the endoplasmic reticulum is not known [43][44][45]. In the absence of ERAP2 protein, cells with distinct ERAP1 haplotypes show substantial differences in HLA-A29 peptidome composition, which demonstrates that ERAP1 is able to directly influence HLA-A29 [43].…”

“…Spanish cases and 2,103 Spanish controls from a previously-described non-infectious uveitis collection [45] and tested with a logistic regression model (replication was defined as Bonferroni-corrected p-value for 2 LD blocks at 5q15 = 0.025). Meta-analysis of Dutch and Spanish cohorts was performed using inverse variance-weighted metaanalysis [46].…”

“…Disease association testing was performed with PLINK v1.07 [23] using a logistic regression model correcting for the top two principal components and sex (Supplementary Figure 1). For replication, the genotype data (n=13) ( Supplementary Table 1) and HLA-A29 status were extracted from 46 Spanish cases and 2,103 Spanish controls from a previously-described non-infectious uveitis collection [24] and tested with a logistic regression model (replication was defined as Bonferroni-corrected p-value for 2 LD blocks at 5q15 = 0.025). Meta-analysis of Dutch and Spanish cohorts was performed using inverse variance-weighted meta-analysis [25].…”

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

“…The relatively high frequency of serine 11 in the JIA patients who did not develop uveitis (Table ) indicates the likely involvement of additional (epi)genetic and environmental factors in uveitis. Only a handful of candidate gene studies , HLA‐specific analyses , and a recent GWAS have investigated uveitis as a phenotype separate from JIA overall, with the latter study identifying HLA–DRB1*1501 as a uveitis risk factor. Genes outside the MHC have also been implicated in JIA‐associated uveitis, including a polymorphism in VTCN1 and variants near the immune genes TRAF1 and C5 .…”

An amino acid motif in HLA-DRβ1 distinguishes patients with uveitis in juvenile idiopathic arthritis

“…Only a handful of candidate gene studies 41 and HLA-specific analyses 4,[17][18][19] have investigated uveitis as a phenotype separate from all JIA. A recent GWAS identified HLA-DRB1*1501 as a risk factor for of non-anterior uveitis, 67 and recent studies in children with anterior uveitis in JIA point toward a role for infiltrated B plasma cells 68 , CD4+ T helper cells 4 , and changes in the ocular fluid microenvironment. 43,69,70 Future, larger genetic studies comparing JIA-uveitis and JIA without uveitis, with and without sex-specific analysis, will likely expand our understanding of uveitis pathogenesis in a number of ways.…”