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

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

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Aminopeptidases / genetics*
  • Aminopeptidases / metabolism
  • Birdshot Chorioretinopathy
  • Case-Control Studies
  • Chorioretinitis / genetics*
  • Chorioretinitis / metabolism
  • European Continental Ancestry Group / genetics
  • Female
  • Genome-Wide Association Study*
  • HLA-A Antigens / genetics
  • Haplotypes
  • Humans
  • Male

Substances

  • HLA-A Antigens
  • HLA-A29 antigen
  • Aminopeptidases
  • ERAP2 protein, human

Supplementary concepts

  • Birdshot chorioretinopathy