Han Xiaoyan, Hua Zhixiang, Chen Han, Yang Jin
Department of Ophthalmology and the Eye Institute, Eye and Ear, Nose, and Throat Hospital, Fudan University, Shanghai, PR China.
Key NHC Key Laboratory of Myopia (Fudan University), Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, PR China.
Medicine (Baltimore). 2025 May 9;104(19):e42357. doi: 10.1097/MD.0000000000042357.
Age-related macular degeneration (AMD) is a leading cause of vision impairment and blindness in older adults, profoundly affecting millions of individuals worldwide. Cathepsins are a crucial class of proteolytic enzymes that participates in multiple biological process. However, the role of cathepsins in AMD still remains unclear. This study aims to probe into the causal relationship between cathepsins and AMD using a 2-sample Mendelian randomization (MR). Instrumental variables associated with exposure (cathepsins) and the outcome (AMD) were sourced from published genome-wide association studies. To estimate the causal effects, methodologies such as inverse variance weighted, MR-Egger, and weighted median estimation (WM) were employed. Reverse MR and multivariate MR analyses were also performed. The elevated levels of cathepsin B significantly increased the risk of dry AMD, with an odds ratio (OR) of 1.068 (95% CI = 1.007-1.133) and a P-value of .029). Sensitivity analyses confirmed the robustness of these findings, with no evidence of heterogeneity or pleiotropy. Reverse MR analyses indicated that total AMD might elevate levels of cathepsin E (OR = 1.04, P = .029). Multivariate MR analysis showed significant associations between specific cathepsins and AMD subtypes, including cathepsin G and cathepsin O with significantly increasing risk. The study revealed a potential causal effect of cathepsin B on AMD, especially dry AMD. These findings provide potential therapeutic targets for AMD, and further research is needed to understand the underlying mechanisms.
年龄相关性黄斑变性（AMD）是老年人视力损害和失明的主要原因，对全球数百万人产生了深远影响。组织蛋白酶是一类关键的蛋白水解酶，参与多种生物学过程。然而，组织蛋白酶在AMD中的作用仍不清楚。本研究旨在使用两样本孟德尔随机化（MR）探究组织蛋白酶与AMD之间的因果关系。与暴露因素（组织蛋白酶）和结局（AMD）相关的工具变量来自已发表的全基因组关联研究。为了估计因果效应，采用了逆方差加权、MR-Egger和加权中位数估计（WM）等方法。还进行了反向MR和多变量MR分析。组织蛋白酶B水平升高显著增加了干性AMD的风险，优势比（OR）为1.068（95%CI = 1.007-1.133），P值为0.029）。敏感性分析证实了这些发现的稳健性，没有异质性或多效性的证据。反向MR分析表明，总的AMD可能会提高组织蛋白酶E的水平（OR = 1.04，P = 0.029）。多变量MR分析显示特定组织蛋白酶与AMD亚型之间存在显著关联，包括组织蛋白酶G和组织蛋白酶O，其风险显著增加。该研究揭示了组织蛋白酶B对AMD，尤其是干性AMD的潜在因果效应。这些发现为AMD提供了潜在的治疗靶点，需要进一步研究以了解其潜在机制。
