Potential therapeutic targets for multisite chronic pain: A proteome-wide Mendelian randomization study

Multisite chronic pain (MCP) is a complex and increasingly prevalent health issue that significantly impairs quality of life. This study aims to identify potential therapeutic targets for MCP through a proteome-wide Mendelian randomization (MR) approach. We conducted a proteome-wide MR to explore the causal associations of plasma proteins with MCP. MCP used data from a genome-wide association study including 387,649 samples. We used protein data from UKB-PPP including 54,219 samples as the discovery analysis, and from Finngen as the replication analysis. Multiple follow-up analyses were used to investigate the potential function of the candidate proteins. Finally, druggability evaluation and phenome-wide MR analysis were used to assess the priority of these targets. We identified 11 plasma proteins significantly associated with MCP. Increased levels of LRP11, BCHE, DAG1, and SUOX exhibited protective effects, while LATS1, CEP170, SLC27A4, HEXIM1, ECM1, C8B, and MST1 increased MCP risk. After multiple validations, ECM1, C8B, LRP11, BCHE has the strongest convincing evidence. Besides, mediation analysis found 4 reliable combinations, revealed the role of plasma proteins in traits influencing MCP. Finally, druggability evaluation and phenome-wide MR indicated that C8B, and BCHE had the highest priority.