Causal relationship between aspirin use and age-related macular degeneration

OBJECTIVE: Although increasing evidence suggests an association between aspirin use and age-related macular degeneration (AMD), the potential causal relationship between them remains controversial. This study aims to explore the causal genetic association and potential mediators between aspirin use and AMD using Mendelian randomisation (MR) analysis. METHODS: A bidirectional, two-sample, two-step MR analysis was performed to assess the potential causal relationships among aspirin use, AMD, and possible mediators. Multivariable MR was additionally performed to estimate the direct effect of aspirin use on AMD after adjusting for mediators. Causal estimates were primarily derived using an inverse variance weighted method. Horizontal pleiotropy, heterogeneity, and stability were evaluated using the MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis. RESULTS: An MR analysis revealed that aspirin use was associated with an increased risk of both early and dry AMD. A mediation analysis indicated that aspirin use is associated with a lower level of serum low-density lipoprotein cholesterol (LDL-C), an elevated serum apolipoprotein A1 (APOA1) concentration, and an increased risk of early and dry AMD. Multivariable MR analysis further showed that after adjusting for LDL-C and APOA1, the direct effect of aspirin on AMD was attenuated to non-significance. CONCLUSION: This study provides robust genetic evidence that aspirin use is associated with an increased risk of early and dry AMD, and demonstrates that this association is fully mediated by decreased serum LDL-C and increased serum APOA1 levels, with no evidence of a direct effect independent of these lipid pathways.