April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
A genome wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy
Author Affiliations & Notes
  • Jonas Kuiper
    Ophthalmology, University medical center utrecht, Utrecht, Netherlands
    Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, Netherlands
  • Jessica Setten
    Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
  • Paul I de Bakker
    Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
    Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA
  • Aniki Rothova
    Ophthalmology, Erasmus University Medical Center, Rotterdam, Netherlands
  • Tuna Mutis
    Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, Netherlands
  • Bobby Koeleman
    Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
  • Footnotes
    Commercial Relationships Jonas Kuiper, None; Jessica Setten, None; Paul de Bakker, None; Aniki Rothova, None; Tuna Mutis, None; Bobby Koeleman, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 6030. doi:
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      Jonas Kuiper, Jessica Setten, Paul I de Bakker, Aniki Rothova, Tuna Mutis, Bobby Koeleman, ; A genome wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6030.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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. HLA-A29 is relatively common in European populations, but only a tiny subset of HLA-A29 positive individuals develops BSCR. Likely, genes other than HLA-A and additional exogenous factors are involved in the development of the disease. To identify BSCR susceptibility genes and to fine-map the association within the MHC region, we conducted a genome-wide association study.

Methods: We performed genome-wide association analysis by genotyping and genome-wide SNP imputation in 96 Dutch and 27 Spanish BSCR cases, and 398 unaffected Dutch and 380 Spanish controls from European ancestry.

Results: 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) = 158, P =6.6 × 10-74). We also identified a novel susceptibility loci at 5q15 near ERAP2 (rs3797796; OR = 2.4 for the T allele, P = 3.6 × 10−8). ERAP2 encodes ERAP2, an aminopeptidase that orchestrates the final step of antigen processing for presentation by HLA class I. The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 5.0 × 10−10). 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.

Conclusions: 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.

Keywords: 539 genetics • 704 retinochoroiditis • 432 autoimmune disease  
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