A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy

Jonas J W Kuiper, Jessica Van Setten, Stephan Ripke, Ruben Van 'T Slot, Flip Mulder, Tom Missotten, G Seerp Baarsma, Laurent C Francioli, Sara L Pulit, Carolien G F De Kovel, Ninette Ten Dam-Van Loon, Anneke I Den Hollander, Paulien Huis in het Veld, Carel B Hoyng, Miguel Cordero-Coma, Javier Martín, Victor Llorenç, Bharti Arya, Dhanes Thomas, Steven C BakkerRoel A Ophoff, Aniki Rothova, Paul I W De Bakker, Tuna Mutis, Bobby P C Koeleman

Research output: Contribution to journalArticleResearchpeer-review


Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

Original languageEnglish
Pages (from-to)6081-7
Number of pages7
JournalHuman Molecular Genetics
Issue number22
Publication statusPublished - 15 Nov 2014


  • Alleles
  • Aminopeptidases/genetics
  • Birdshot Chorioretinopathy
  • Case-Control Studies
  • Chorioretinitis/genetics
  • European Continental Ancestry Group/genetics
  • Female
  • Genome-Wide Association Study
  • HLA-A Antigens/genetics
  • Haplotypes
  • Humans
  • Male


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