학술논문
A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy
Document Type
article
Author
Kuiper, Jonas JW; Van Setten, Jessica; Ripke, Stephan; Van ‘T Slot, Ruben; Mulder, Flip; Missotten, Tom; Baarsma, G Seerp; Francioli, Laurent C; Pulit, Sara L; De Kovel, Carolien GF; Loon, Ninette Ten Dam-Van; Hollander, Anneke I Den; Veld, Paulien Huis in het; Hoyng, Carel B; Cordero-Coma, Miguel; Martín, Javier; Llorenç, Victor; Arya, Bharti; Thomas, Dhanes; Bakker, Steven C; Ophoff, Roel A; Rothova, Aniki; De Bakker, Paul IW; Mutis, Tuna; Koeleman, Bobby PC
Source
Human Molecular Genetics. 23(22)
Subject
Language
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.