Erap1, erap2, and two copies of hla-aw19 alleles increase the risk for birdshot chorioretinopathy in hla-a29 carriers

Sahar Gelfman, Dominique Monnet, Ann J. Ligocki, Thierry Tabary, Arden Moscati, Xiaodong Bai, Jan Freudenberg, Blerta Cooper, Jack A. Kosmicki, Sarah Wolf, Manuel A.R. Ferreira, John Overton, Jonathan Weyne, Eli A. Stahl, Aris Baras, Carmelo Romano, Jacques H.M. Cohen, Giovanni Coppola, Antoine Brezin

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


PURPOSE. Birdshot chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers. METHODS. We sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29-positive controls to determine genome-wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk. RESULTS. Carrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, -A30, -A31, and -A33) increases the risk for BSCR (odds ratio [OR] = 4.44; P = 2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n = 45,386; OR > 2.5; P < 1.3e-06). We also confirm that ERAP1 and ERAP2 haplotypes modulate disease risk. A meta-analysis with an independent dataset confirmed that ERAP1 and ERAP2 haplotypes modulate the risk for disease at a genome-wide significant level: ERAP1-rs27432 (OR = 2.46; 95% confidence interval [CI], 1.85-3.26; P = 4.07e-10), an expression quantitative trait locus (eQTL) decreasing ERAP1 expression; and ERAP2-rs10044354 (OR = 1.95; 95% CI, 1.55-2.44; P = 6.2e- 09), an eQTL increasing ERAP2 expression. Furthermore, ERAP2-rs2248374 that disrupts ERAP2 expression is protective (OR = 0.56; 95% CI, 0.45-0.70; P = 2.39e-07). BSCR risk is additively increased when combining ERAP1/ERAP2 risk genotypes with two copies of HLA-Aw19 alleles (OR = 13.53; 95% CI, 3.79-54.77; P = 1.17e-05). CONCLUSIONS. The genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2-specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.

Original languageEnglish
Article numbere2778043
JournalInvestigative Ophthalmology and Visual Science
Issue number14
StatePublished - Nov 2021
Externally publishedYes


  • Birdshot
  • ERAP1
  • ERAP2
  • HLA-A33
  • HLA-Aw19


Dive into the research topics of 'Erap1, erap2, and two copies of hla-aw19 alleles increase the risk for birdshot chorioretinopathy in hla-a29 carriers'. Together they form a unique fingerprint.

Cite this