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 - Ten Dam-Van Loon, Ninette
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
N1 - © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
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 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.
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 × 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.
KW - Alleles
KW - Aminopeptidases/genetics
KW - Birdshot Chorioretinopathy
KW - Case-Control Studies
KW - Chorioretinitis/genetics
KW - European Continental Ancestry Group/genetics
KW - Female
KW - Genome-Wide Association Study
KW - HLA-A Antigens/genetics
KW - Haplotypes
KW - Humans
KW - Male
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 -