TY - JOUR
T1 - A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy
AU - Kuiper, Jonas J.W.
AU - Van Setten, Jessica
AU - Ripke, Stephan
AU - Van 'T Slot, Ruben
AU - Mulder, Flip
AU - Missotten, Tom
AU - Baarsma, G. Seerp
AU - Francioli, Laurent C.
AU - Pulit, Sara L.
AU - De Kovel, Carolien G.F.
AU - Dam-Van Loon, Ninette Ten
AU - Den Hollander, Anneke I.
AU - Huis in het Veld, Paulien
AU - Hoyng, Carel B.
AU - Cordero-Coma, Miguel
AU - Martín, Javier
AU - Llorenç, Victor
AU - Arya, Bharti
AU - Thomas, Dhanes
AU - Bakker, Steven C.
AU - Ophoff, Roel A.
AU - Rothova, Aniki
AU - De Bakker, Paul I.W.
AU - Mutis, Tuna
AU - Koeleman, Bobby P.C.
PY - 2014/11/15
Y1 - 2014/11/15
N2 - 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 × 10-74). 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 × 10-8) and at 14q32.31 in theTECPR2 gene (rs150571175;OR 5 6.1,95%CI 3.2-11.7, for theAallele,P = 3.2 × 10-8). The association nearERAP2was 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.
AB - 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 × 10-74). 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 × 10-8) and at 14q32.31 in theTECPR2 gene (rs150571175;OR 5 6.1,95%CI 3.2-11.7, for theAallele,P = 3.2 × 10-8). The association nearERAP2was 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.
UR - http://www.scopus.com/inward/record.url?scp=84911388736&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddu307
DO - https://doi.org/10.1093/hmg/ddu307
M3 - Article
C2 - 24957906
SN - 0964-6906
VL - 23
SP - 6081
EP - 6087
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 22
ER -