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 perform 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 (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 the risk for disease within our HLA-A29 controlled cohort. 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% CI 1.85-3.26; p=4.07e-10), an 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.

中文翻译：

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ERAP1、ERAP2 和 HLA-Aw19 等位基因的两个拷贝会增加 HLA-A29 携带者发生鸟击性脉络膜视网膜病变的风险

目的：鸟类脉络膜视网膜病变 (BSCR) 与 HLA-A29 密切相关。本研究旨在阐明 HLA-A29 携带者中 BSCR 的遗传修饰物。方法：我们对迄今为止最大的 BSCR 队列进行了测序，包括 286 个病例和 108 个 HLA-A29 阳性对照，以进行全基因组常见和罕见变异关联。我们进一步对病例的 HLA 等位基因和欧洲血统的 45,386 个 HLA-A29 对照进行了分型，以确定与 BSCR 风险相关的 HLA 等位基因。结果：携带属于 HLA-Aw19 广泛抗原家族（包括 HLA-A29、A30、A31 和 A33）的第二个等位基因会增加 BSCR 的风险（OR=4.44，p=2.2e-03）。该结果通过将等位基因频率与大型 HLA-A29 控制队列进行比较得到验证（n=45,386，OR>2.5，p<1.3e-06）。我们还确认 ERAP1 和 ERAP2 单倍型在我们的 HLA-A29 对照队列中调节疾病风险。对独立数据集的荟萃分析证实 ERAP1 和 ERAP2 单倍型在全基因组显着水平上调节疾病风险：ERAP1-rs27432（OR 2.46；95% CI 1.85-3.26；p=4.07e-10）， eQTL 降低 ERAP1 表达，而 ERAP2-rs10044354（OR 1.95；95% CI 1.55-2.44；p=6.2e-09）是一种增加 ERAP2 表达的 eQTL。此外，破坏 ERAP2 表达的 ERAP2-rs2248374 具有保护作用（OR 0.56；95% CI [0.45-0.70]；p=2.39e-07）。当 ERAP1/ERAP2 风险基因型与两个 HLA-Aw19 等位基因拷贝相结合时，BSCR 风险会增加（OR 13.53；95% CI 3.79-54.77，p=1.17e-05）。结论：增加 BSCR 风险的遗传因素表现出一种处理增加的模式，以及增加 ERAP2 特异性肽的呈递。这暗示了一种机制，其中超过肽呈递阈值会激活 A29 携带者脉络膜中的免疫反应。