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<sup>-74</sup>). 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<sup>-8</sup>) and at 14q32.31 in theTECPR2 gene (rs150571175;OR 5 6.1,95%CI 3.2-11.7, for theAallele,P = 3.2 × 10<sup>-8</sup>). The association nearERAP2was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10<sup>-9</sup>). 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.

doi.org/10.1093/hmg/ddu307, hdl.handle.net/1765/81987
Human Molecular Genetics
Erasmus MC: University Medical Center Rotterdam

Kuiper, J.J.W, van Setten, J, Ripke, S, van 't Slot, R, Mulder, F, Missotten, T, … Koeleman, B.P.C. (2014). A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy. Human Molecular Genetics, 23(22), 6081–6087. doi:10.1093/hmg/ddu307