Uncovering drug-associated risk signals for neovascular age-related macular degeneration: an integrative pharmacovigilance and proteogenomic study.

OBJECTIVES

To identify drug-associated risk signals for neovascular age-related macular degeneration (nAMD) and explore their biological basis.

METHODS

We analysed the US FDA Adverse Event Reporting System (FAERS) to detect drugs with disproportionate nAMD reporting. Drug targets were mapped and causality was assessed by integrating summary-based Mendelian randomisation (SMR) and colocalisation analyses using cis-pQTL data. Single-cell RNA sequencing from nAMD patients evaluated cell type-specific gene expression. Protein-protein interaction and pathway enrichment analyses elucidated underlying mechanisms.

RESULTS

FAERS analysis identified five drugs (apixaban, carbamazepine, latanoprost, rituximab and semaglutide) significantly associated with higher reporting risks of nAMD. SMR implicated six genes (IGFBP6, MAPKAPK2, NFKB1, RGMA, RNASE1 and WARS1) in nAMD risk, with evidence supporting colocalisation for WARS1. Most candidate genes were predominantly expressed in vascular remodelling endothelial cells, while WARS1 was also highly specific to monocytes. Enrichment analysis highlighted their critical involvement in immune and inflammatory responses, particularly within the Toll-like receptor, TNF and NF-kappa B signalling pathways.

CONCLUSIONS

This study suggests a potential association between specific drugs and nAMD and reveals six genes as their possible molecular basis, thereby providing prioritised candidate targets and testable biological hypotheses for subsequent experimental validation.