Age-related macular degeneration (AMD) is the leading cause of severe irreversible central vision loss in individuals over 65 years old. Genome-wide association studies (GWASs) have shown that the region at chromosome 10q26, where the age-related maculopathy susceptibility (ARMS2/LOC387715) and HtrA serine peptidase 1 (HTRA1) genes are located, represents one of the strongest associated loci for AMD. However, the underlying biological mechanism of this genetic association has remained elusive. In this article, we extensively review the literature by us and others regarding the ARMS2/HTRA1 risk alleles and their functional significance. We also review the literature regarding the presumed function of the ARMS2 protein and the molecular processes of the HTRA1 protein in AMD pathogenesis in vitro and in vivo, including those of transgenic mice overexpressing HtrA1/HTRA1 which developed Bruch's membrane (BM) damage, choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV), similar to human AMD patients. The elucidation of the molecular mechanisms of the ARMS2 and HTRA1 susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.

年龄相关性黄斑变性 (AMD) 是 65 岁以上个体严重不可逆中心视力丧失的主要原因。全基因组关联研究 (GWAS) 表明，年龄相关性黄斑病变易感性 ( ARMS2/LOC387715 ) 和 HtrA 丝氨酸肽酶 1 ( HTRA1 ) 基因所在的染色体 10q26 区域是 AMD 最强相关位点之一。然而，这种遗传关联的潜在生物学机制仍然难以捉摸。在本文中，我们广泛回顾了我们和其他人关于ARMS2/HTRA1风险等位基因及其功能意义的文献。我们还回顾了有关 ARMS2 蛋白的推测功能和HTRA1 蛋白在 AMD 体外和体内发病机制中的分子过程的文献，包括过度表达 HtrA1/HTRA1 的转基因小鼠，这些小鼠出现布鲁赫膜 (BM) 损伤、脉络膜新生血管形成(CNV) 和息肉样脉络膜血管病变 (PCV)，与人类 AMD 患者相似。对ARMS2和HTRA1易感位点分子机制的阐明已经开始解开 AMD 病理生理学基础的复杂生物学途径，为治疗提供新的可测试范式。