Cathepsins and age-related macular degeneration: A Mendelian randomization study unveiling causal relationships

Abstract

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.

Keywords: Mendelian randomization; age-related macular degeneration; cathepsin.

Figure 1.

Flowchart of the study design.

Figure 2.

Scatter plots of MR analysis for cathepsins and AMD subtypes. Each point represents the effect of a SNP on both the exposure (cathepsins) and the outcome (AMD subtypes). Different colored regression lines indicate causal effects estimated using various algorithms. AMD = Age-related macular degeneration, MR = Mendelian randomization SNP = single-nucleotide polymorphism.

Figure 3.

Forest plot of OR in multivariate MR analysis for the association between cathepsins and AMD. Linear forest plot illustrating the OR from the multivariate MR analysis for the association between cathepsins and AMD. Each horizontal line represents an OR with its corresponding confidence interval, providing a clear visualization of effect sizes across different models or variables. Asterisks (*) indicate statistically significant results with P-values < .05. AMD = age-related macular degeneration, MR = Mendelian randomization, OR = odds ratio.