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

Abstract

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- 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 × 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.

Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties

“…whereas individuals that carry ERAP2 allotypes that lead to no protein expression, are more often homozygous for the most active ERAP1 allotype (allotype 2). This is in line with previous genetic analysis of co-occurrence of ERAP1-ERAP2 haplotypes (11). Thus, it appears that some balancing selection may exist that attempts to normalize total aminopeptidase activity in the ER.…”

“…The latter affects ERAP2 expression levels through splicing a transcript variant susceptible to nonsensemediated RNA decay (36). Of the four possible combinations, we were able to detect only two in our population sample, the [G,A] allotype (defined as allotype A in (36) (11) in Dutch and Spanish controls, we were interested to see if the ERAP1 and ERAP2 allotypes correlate in this global data set. Thus, we calculated the distribution of ERAP1 allotypes in each group of individuals carrying a particular ERAP2 allotype (Supplemental Table 4).…”

“…Most importantly, several recent cell-based studies using proteomic approaches have provided strong support that changes in ERAP1 activity due to polymorphic variation are to a large extent translated to changes in antigen presentation (55). Also, although the expression of ERAP1 mediated by splice interfering variants (19) is in linkage disequilibrium with variants that encode enzymatically distinct allotypes, genetic association studies have shown that for some (HLA-associated) conditions the disease risk is primarily mapped to enzymatic activity (11). Thus, although MHCI binding is the dominant filter, changes in ERAP1 activity are relevant to antigen presentation and probably underlie known disease associations.…”

“…Here, the genetic signature of the ERAP1 associations is the often epistasis with HLA class I alleles, which emphasizes the critical role of ERAP1 in HLA class I antigen presentation (7)(8)(9)(10). The genetic association with ERAP1 SNPs and inflammatory diseases such as HLA-B27-associated Ankylosing Spondylitis, HLA-B51-associated Behçet's Disease and HLA-A29-associated Birdshot Uveitis led to the hypothesis that these conditions are driven by pathogenic changes in antigen presentation as a direct result of alterations in substrate preferences or activity of ERAP1 (11)(12)(13)(14). Several of these ERAP1 SNPs have been described to affect the function of the enzyme (15,16).…”

“…Several of these ERAP1 SNPs have been described to affect the function of the enzyme (15,16). Mechanisms proposed to underlie this effect include direct interactions with the substrate (17), effects on the conformational dynamics of the enzyme (18) and effects on the protein expression level (19,20), or combinations of these (11). However, not all of the possible combinations of the 9 most common coding SNPs (i.e.…”