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Hum Mol Genet DOI:10.1093/hmg/ddu307

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

Publication TypeJournal Article
Year of Publication2014
AuthorsKuiper, JJW, van Setten, J, Ripke, S, Slot, RVan 'T, Mulder, F, Missotten, T, G Baarsma, S, Francioli, LC, Pulit, SL, De Kovel, CGF, Van Loon, NTen Dam-, Hollander, AI den, Veld, PHuis in he, Hoyng, CB, Cordero-Coma, M, Martín, J, Llorenç, V, Arya, B, Thomas, D, Bakker, SC, Ophoff, RA, Rothova, A, de Bakker, PIW, Mutis, T, Koeleman, BPC
JournalHum Mol Genet
Date Published2014 Nov 15
KeywordsAlleles, Aminopeptidases, Case-Control Studies, Chorioretinitis, European Continental Ancestry Group, Female, Genome-Wide Association Study, Haplotypes, HLA-A Antigens, Humans, Male

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.


Alternate JournalHum. Mol. Genet.
PubMed ID24957906
PubMed Central IDPMC4204766
Grant ListMH090553 / MH / NIMH NIH HHS / United States