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Jonas Kuiper, Jessica Setten, Paul I de Bakker, Aniki Rothova, Tuna Mutis, Bobby Koeleman, ; A genome wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6030.
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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. HLA-A29 is relatively common in European populations, but only a tiny subset of HLA-A29 positive individuals develops BSCR. Likely, genes other than HLA-A and additional exogenous factors are involved in the development of the disease. To identify BSCR susceptibility genes and to fine-map the association within the MHC region, we conducted a genome-wide association study.
We performed genome-wide association analysis by genotyping and genome-wide SNP imputation in 96 Dutch and 27 Spanish BSCR cases, and 398 unaffected Dutch and 380 Spanish controls from European ancestry.
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) = 158, P =6.6 × 10-74). We also identified a novel susceptibility loci at 5q15 near ERAP2 (rs3797796; OR = 2.4 for the T allele, P = 3.6 × 10−8). ERAP2 encodes ERAP2, an aminopeptidase that orchestrates the final step of antigen processing for presentation by HLA class I. The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 5.0 × 10−10). 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.
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