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

Jonas J W Kuiper, Jessica van Setten, Matthew Devall, Mircea Cretu-Stancu, Sanne Hiddingh, Roel A Ophoff, Tom O A R Missotten, Mirjam van Velthoven, Anneke I Den Hollander, Carel B Hoyng, Edward James, Emma Reeves, Miguel Cordero-Coma, Alejandro Fonollosa, Alfredo Adán, Javier Martín, Bobby P C Koeleman, Joke H de Boer, Sara L Pulit, Ana MárquezTimothy R D J Radstake

Research output: Contribution to journalArticleResearchpeer-review

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 (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.

Original languageEnglish
Pages (from-to)4333-4343
Number of pages11
JournalHuman Molecular Genetics
Volume27
Issue number24
DOIs
Publication statusPublished - 15 Dec 2018

Keywords

  • Aminopeptidases/genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • HLA-A Antigens/genetics
  • Haplotypes/genetics
  • Humans
  • Male
  • Minor Histocompatibility Antigens/genetics
  • Minor Histocompatibility Loci/genetics
  • Polymorphism, Single Nucleotide/genetics
  • Uveitis/genetics

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