1. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy
- Author
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Kuiper, J.J.W. (Jonas), Setten, J. (Jessica) van, Ripke, S. (Stephan), Slot, R. (Ruben) van 't, Mulder, F. (Flip), Missotten, T. (Tom), Baarsma, G.S. (Seerp), Francioli, L.C. (Laurent), Pulit, S.L. (Sara), Kovel, C.G.F. (Carolien) de, Dam-Van Loon, N.T. (Ninette Ten), Hollander, A.I. (Anneke), Huis in het Veld, P. (Paulien), Hoyng, C.B. (Carel), Cordero-Coma, M. (Miguel), Martín, J. (Javier), Llorenç, V. (Victor), Arya, B. (Bharti), Thomas, D. (Dhanes), Bakker, S.C. (Steven), Ophoff, R.A. (Roel), Rothová, A. (Aniki), Bakker, P.I.W. (Paul) de, Mutis, T. (Tuna), Koeleman, B.P.C. (Bobby), Kuiper, J.J.W. (Jonas), Setten, J. (Jessica) van, Ripke, S. (Stephan), Slot, R. (Ruben) van 't, Mulder, F. (Flip), Missotten, T. (Tom), Baarsma, G.S. (Seerp), Francioli, L.C. (Laurent), Pulit, S.L. (Sara), Kovel, C.G.F. (Carolien) de, Dam-Van Loon, N.T. (Ninette Ten), Hollander, A.I. (Anneke), Huis in het Veld, P. (Paulien), Hoyng, C.B. (Carel), Cordero-Coma, M. (Miguel), Martín, J. (Javier), Llorenç, V. (Victor), Arya, B. (Bharti), Thomas, D. (Dhanes), Bakker, S.C. (Steven), Ophoff, R.A. (Roel), Rothová, A. (Aniki), Bakker, P.I.W. (Paul) de, Mutis, T. (Tuna), and Koeleman, B.P.C. (Bobby)
- 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 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 re
- Published
- 2014
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