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

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.

Figure 1.

Association tests within the MHC region to birdshot chorioretinopathy. The strongest MHC signal mapped to HLA-A*29:02 allele. The shading depicts the strength of the correlation (r²) between HLA-A*29:02 (red diamond) and the SNPs tested in the region. Gene positions are obtained from the human genome build 37 (GRCh37/hg19).

Figure 2.

Expression of ERAP2 and LNPEP in CEPH control and BSCR according to rs10044354 genotype. B-cell lines from individuals from the CEPH panel (13) and five BSCR patients were lysed and ERAP2 and LNPEP expression was assessed after SDS–PAGE and western blotting with antibodies to ERAP2 and LNPEP. The endogenous levels of both α- and β-tubulin total protein were analyzed as a loading control. The horizontal lines indicate the means. Kruskal–Wallis test with Dunn's multiple-comparison post hoc test was used to assess differences in the levels of ERAP2 between B-cell line groups according to rs10044354 genotype.