Potential drug targets for peripheral artery disease identified through Mendelian randomization analysis.

Abstract

Introduction: Peripheral Artery Disease (PAD) is a common cardiovascular condition marked by peripheral artery stenosis or occlusion. Despite treatment advancements, patients will still face vascular complications, highlighting the need for innovative therapies. Human proteins play crucial roles in biology and drug research. Mendelian randomization (MR) analysis, a gene-based method, is increasingly used in drug target identification. This study aims to identify PAD-associated plasma proteins through MR analysis for potential therapies.

Methods: We first used GWAS data and seven pQTL datasets to identify plasma proteins causally linked to PAD through MR analysis. Then, we performed KEGG pathway enrichment analysis, Bayesian colocalization analysis, and MR-BMA analysis were carried out to investigate mechanisms and prioritize these proteins. Finally, we assessed the druggability of the target proteins using the DrugBank database.

Results: MR analysis found four plasma proteins causally linked to PAD: MMP3 positively correlated with PAD, while CASS4, ISG15, and MMP1 exhibited negative associations. Bayesian colocalization analysis confirmed these relationships, and the MR-BMA analysis prioritized MMP1 as the main target. KEGG pathway enrichment analysis highlighted lipid metabolism and atherosclerosis pathways as central to these drug targets. The druggability evaluation indicated that drugs targeting these proteins are either in development or already in clinical use.

Conclusion: This study integrates genetic and proteomic data to identify therapeutic targets for PAD and evaluate their potential for drug development. The prioritization of MMP1 and ISG15 as key targets shows promise for PAD treatment, but further validation and clinical exploration of these findings are needed.