Kuiper Jonas J W, Van Setten Jessica, Ripke Stephan, Van 'T Slot Ruben, Mulder Flip, Missotten Tom, Baarsma G Seerp, Francioli Laurent C, Pulit Sara L, De Kovel Carolien G F, Ten Dam-Van Loon Ninette, Den Hollander Anneke I, Huis in het Veld Paulien, Hoyng Carel B, Cordero-Coma Miguel, Martín Javier, Llorenç Victor, Arya Bharti, Thomas Dhanes, Bakker Steven C, Ophoff Roel A, Rothova Aniki, De Bakker Paul I W, Mutis Tuna, Koeleman Bobby P C
Department of Ophthalmology, Department of Clinical Chemistry and Hematology.
Department of Medical Genetics.
Hum Mol Genet. 2014 Nov 15;23(22):6081-7. doi: 10.1093/hmg/ddu307. Epub 2014 Jun 22.
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.
鸟枪弹样脉络膜视网膜病变（BSCR）是一种罕见的自身免疫性葡萄膜炎，可导致严重视力损害。有趣的是，超过95%的病例携带HLA - A29等位基因，这是人类疾病中记录最强的HLA关联。我们对96例荷兰和27例西班牙患者，以及398名无关的荷兰人和380名西班牙对照进行了全基因组关联研究。通过在经典HLA位点进行高分辨率归因对主要MHC关联进行精细定位，确定HLA - A*29:02为主要MHC关联（优势比（OR）= 157.5，95%可信区间91.6 - 272.6，P = 6.6×10^(-74)）。我们还在ERAP2附近的5q15（rs7705093；对于T等位基因，OR = 2.3，95%可信区间1.7 - 3.1，P = 8.6×10^(-8)）和TECPR2基因的14q32.31（rs150571175；对于A等位基因，OR = 6.1，95%可信区间3.2 - 11.7，P = 3.2×10^(-8)）发现了两个新的易感位点。ERAP2附近的关联在一个独立的英国病例对照样本中得到证实（合并荟萃分析P = 1.7×10^(-9)）。功能分析表明，ERAP2附近多态性的风险等位基因与B细胞中ERAP2的高mRNA和蛋白表达密切相关。这项研究进一步明确了BSCR中一个极其强大的MHC风险成分，并检测到一种影响内质网中肽加工的新疾病机制的证据。
