Biology subjects

de Boer, J. H.

Publications and source records attributed to de Boer, J. H..

2 recordsLinked to original sources

bioRxiv2018

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

Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed \"MHC-I-opathy\" family. Genetic studies have pinpointed the ERAP1 and ERAP2 genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression. We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC-I-opathies. We show that the risk ERAP1 haplotype conferred significantly altered expression of ERAP1 isoforms in transcriptomic data (n=360), resulting in lowered protein expression and distinct enzymatic activity. Both the association for rs10044354 (meta-analysis: OR[95% CI]=2.07[1.58-2.71], p=1.24 x 10(-7)) and rs2287987 (OR[95% CI]: =2.01 [1.51-2.67], p=1.41 x 10(-6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2,103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either SNP alone (meta-analysis: p=3.9 x 10(-9)). Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n=3,353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

genetics↗

bioRxiv2017

An Amino Acid Motif In HLA-DRB1 Distinguishes Patients With Uveitis In Juvenile Idiopathic Arthritis

ObjectivesUveitis 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.\n\nMethodsTwo cohorts of JIA patients with ophthalmological follow-up were separately genotyped and then imputed 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. We used a reverse immunology approach to model antigen presentation at 13 common HLA-DRB1 allotypes.\n\nResultsWe 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). We found the serine-11 signal to be 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 the HLA-DRB1 protein; 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-DRB1 allotypes with the YST-motif.\n\nConclusionOur findings highlight a genetically distinct, sexually-dimorphic feature of JIA-uveitis compared to JIA without uveitis in HLA-DRB1. The association indicates the potential involvement for antigen presentation by HLA-DRB1 in the development of uveitis in JIA.

genetics↗