Publication Date:
2014-10-22
Description:
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 x 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 x 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 x 10 –8 ). The association near ERAP2 was confirmed in an independent British case–control samples (combined meta-analysis P = 1.7 x 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.
Print ISSN:
0964-6906
Electronic ISSN:
1460-2083
Topics:
Biology
,
Medicine
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