Kuiper, Jonas J WSetten, Jessica vanDevall, MatthewCretu-Stancu, MirceaHiddingh, SanneOphoff, Roel AMissotten, Tom O A RVelthoven, Mirjam vanDen Hollander, Anneke IHoyng, Carel BJames, EdwardReeves, EmmaCordero-Coma, MiguelFonollosa, AlejandroAdán, AlfredoMartín, JavierKoeleman, Bobby P CBoer, Joke H dePulit, Sara LMárquez, AnaRadstake, Timothy R D J2023-01-252023-01-252018http://hdl.handle.net/10668/12943Birdshot 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 (major histocompatibility complex class I)-opathy' family. Genetic studies have pinpointed the endoplasmic reticulum aminopeptidase (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: odds ratio (OR) [95% CI]=2.07[1.58-2.71], P = 1.24 × 10(-7)) and rs2287987 (OR[95% CI]: =2.01[1.51-2.67], P = 1.41 × 10(-6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either variant 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 = 3353). 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.enAttribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/AminopeptidasesFemaleGenetic Association StudiesGenetic Predisposition to DiseaseGenotypeHLA-A AntigensHaplotypesHumansMaleMinor Histocompatibility AntigensMinor Histocompatibility LociPolymorphism, Single NucleotideUveitisresearch article30215709open access10.1093/hmg/ddy3191460-2083PMC6276832https://academic.oup.com/hmg/article-pdf/27/24/4333/27013295/ddy319.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276832/pdf