You are here

Human molecular genetics 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, JJ, van Setten, J, Ripke, S, Van't Slot, R, Mulder, F, Missotten, T, Baarsma, GS, Francioli, LC, Pulit, SL, de Kovel, CG, Ten Dam-van Loon, N, den Hollander, AI, Huis In Het Veld, P, Hoyng, CB, Cordero-Coma, M, Martín, J, Llorenç, V, Arya, B, Thomas, D, Bakker, SC, Ophoff, RA, Rothova, A, de Bakker, PI, Mutis, T, Koeleman, BP
JournalHuman molecular genetics
Date Published2014/06/22

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.