Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD.

全基因组关联研究发现，染色体 10q26 (Chr10) 位点包含年龄相关性黄斑病变易感性 2 ( ARMS2 ) 和高温需求 A 丝氨酸肽酶 1 ( HTRA1 ) 基因，是年龄相关性黄斑病变最强的遗传风险因素。黄斑变性 (AMD) [LG Fritsche 等人， Annu。基因组学牧师 嗯。热内特. 15, 151–171, (2014)]。迄今为止，由于疾病相关变异之间存在高度连锁不平衡，因此很难将该区域内的任何特定单核苷酸多态性（SNP）、单倍型或基因归为因果关系[J.雅各布斯多蒂尔等人。是。 J.哼。热内特. 77, 389–407 (2005); A.里维拉等人。哼。摩尔。热内特. 14, 3227–3236 (2005)]。在这里，我们发现HTRA1信使 RNA (mRNA) 在视网膜色素上皮 (RPE) 中减少，但在 10q26 位点具有纯合风险的人类供体来源的神经视网膜或脉络膜组织中没有减少。这种组织特异性减少是由与ARMS2内含子重叠的非编码顺式调控元件的存在介导的，该元件包含潜在的 Lhx2 转录因子结合位点，该位点被风险变异 rs36212733 破坏。在 Chr10 非风险供体中，HtrA1 蛋白在 RPE-Bruch 膜 (BM) 界面中随着年龄的增长而增加，但在 10q26 位点具有纯合风险的供体中却没有增加。我们认为，HtrA1（一种细胞外伴侣和丝氨酸蛋白酶）的作用是在衰老过程中维持 RPE-BM 界面的最佳完整性，并且 Chr10 风险供体中HTRA1 mRNA 和蛋白质表达的减少会损害这种保护功能，导致风险增加AMD 发病机制。 在高危患者中，HtrA1 增强而非抑制应被视为 AMD 的潜在治疗方法。