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Hum Mol Genet. 2014 Nov 15;23(22):6081-7. doi: 10.1093/hmg/ddu307. Epub 2014 Jun 22.

A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.

Author information

  • 1Department of Ophthalmology, Department of Clinical Chemistry and Hematology.
  • 2Department of Medical Genetics.
  • 3Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 4The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
  • 5Department of Ophthalmology.
  • 6Department of Ophthalmology and Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
  • 7Department of Ophthalmology and.
  • 8Unidad de Uveitis. Servicio de Oftalmología, Hospital Universitario de León, León, Spain.
  • 9Instituto de Parasitología y Biomedicina López-Neyra, IPBLN, CSIC, Granada, Spain.
  • 10Institut Clinic d'Oftalmologia (ICOF), Hospital Clinic de Barcelona, Barcelona, Spain.
  • 11Moorfields Eye Hospital NHS Foundation Trust, London, UK.
  • 12Department of Psychiatry, Rudolph Magnus Institute of Neuroscience.
  • 13Department of Psychiatry, Rudolph Magnus Institute of Neuroscience, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA and.
  • 14Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 15Department of Medical Genetics, Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 16Department of Clinical Chemistry and Hematology.
  • 17Department of Medical Genetics,


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.

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