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

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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 classicalHLA loci, identified HLA-A*29:02 as the principalMHCassociation (odds ratio (OR) 5 157.5, 95% CI 91.6-272.6, P = 6.6 × 10-74). We also identified two novel susceptibility loci at 5q15 nearERAP2 (rs7705093;OR 5 2.3,95%CI 1.7-3.1, for the T allele,P = 8.6 × 10-8) and at 14q32.31 in theTECPR2 gene (rs150571175;OR 5 6.1,95%CI 3.2-11.7, for theAallele,P = 3.2 × 10-8). The association nearERAP2was 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)6081-6087
Number of pages7
JournalHuman Molecular Genetics
Issue number22
Publication statusPublished - 15 Nov 2014

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