Roles of plasma proteins in mediating the causal effect of the lipid species on gastric cancer and exploring potential drug targets for gastric cancer：insights from proteomic and two-step mendelian randomization and macromolecular docking

Abstract

Background The change of plasma lipid species has close contacts with gastric cancer (GC). However, the specific mechanism still needs to explore further. Objectives We aim to utilize plasma proteins to decipher the association between lipid species and GC, and seek possible drug targets for GC. Methods A two-step mendelian randomization (MR) is conducted to identify the causal relationship among 179 lipid species, 4907 plasma proteins and GC. We employ the summary mendelian randomization (SMR) and colocalization to explore relationship between plasma proteins and GC. We use one protein data including 35559 individuals as discovery group, meanwhile the other one from 54219 subjects as validation group. MR is performed to identify the association between lipid species and GC or plasma proteins. Based on chosen proteins, we use macromolecular docking to find potential components as ligands. Results MR identifies the causality between 12 lipid species and GC, 3 proteins and GC, 2 lipid species and 2 proteins. After the test of propagation of error method, we conclude that CCDC80 protein mediates (30.8%; 95% confidents interval (Cl), 6.4%-64.0%) of the association between Diacylglycerol (16:1_18:1) and GC. For CCDC80, we choose 4 components including 2,3,7,8-Tetrachlorodibenzo-P-dioxin, Benzo[a]pyrene, Bisphenol A, Valproic Acid as potential drugs. Conclusion Our study suggests that CCDC80, a drug target, is a mediator between Diacylglycerol (16:1_18:1) and GC, which may guide a novel direction for GC treatment.