| Literature DB >> 24957906 |
Jonas J W Kuiper1, Jessica Van Setten2, Stephan Ripke3, Ruben Van 'T Slot2, Flip Mulder2, Tom Missotten4, G Seerp Baarsma4, Laurent C Francioli2, Sara L Pulit2, Carolien G F De Kovel2, Ninette Ten Dam-Van Loon5, Anneke I Den Hollander6, Paulien Huis in het Veld7, Carel B Hoyng7, Miguel Cordero-Coma8, Javier Martín9, Victor Llorenç10, Bharti Arya11, Dhanes Thomas11, Steven C Bakker12, Roel A Ophoff13, Aniki Rothova14, Paul I W De Bakker15, Tuna Mutis16, Bobby P C Koeleman17.
Abstract
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.Entities:
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Year: 2014 PMID： 24957906 PMCID： PMC4204766 DOI： 10.1093/hmg/ddu307
Source DB: PubMed Journal: Hum Mol Genet ISSN： 0964-6906 Impact factor: 6.150