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
AU - Pulit, Sara L.
AU - de Kovel, Carolien G.F.
AU - ten Dam-van Loon, Ninette
AU - Den Hollander, Anneke I.
AU - Veld, Paulien Huis In Het
AU - Hoyng, Carel B.
AU - Cordero-Coma, Miguel
AU - Martin, Javier
AU - Llorenc, 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
Y1 - 2014
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 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 Aallele, 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.
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 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 Aallele, 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.
KW - CROHNS-DISEASE SUSCEPTIBILITY
KW - ANKYLOSING-SPONDYLITIS
KW - ENDOPLASMIC-RETICULUM
KW - RHEUMATOID-ARTHRITIS
KW - HUMAN HEIGHT
KW - RISK LOCI
KW - RETINOCHOROIDOPATHY
KW - AUTOPHAGY
KW - VARIANTS
KW - MULTIPLE
U2 - 10.1093/hmg/ddu307
DO - 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 -