Causal effect between immunocytes, plasma metabolites, and hepatocellular carcinoma: a bidirectional two-sample Mendelian randomization study and mediation analysis

Background Hepatocellular carcinoma (HCC) is a primary malignant liver tumor, characterized by a notably low 5-year survival rate and a high mortality rate globally. This study aimed to investigate the causal effect between immune cell phenotypes, plasma metabolites, and HCC. Methods Summary statistics of 731 immunocytes traits (N = 3,757), 1,400 plasma metabolite traits (N = 8,299) and HCC trait (N = 197,611) were obtained from publicly available genome-wide association studies (GWAS). Two-sample Mendelian randomization (MR) analysis was applied to infer the causal links using inverse variance-weighted, simple mode, MR-Egger, weighted median, and weighted mode. Several sensitivity analyses were performed to ensure reliable MR results. Finally, we used mediation analysis to identify the pathway from immunocytes to mediated by plasma metabolites. Results Causal relationships were identified among the 20 immune cell phenotypes and HCC with one exhibiting reverse causality. Additionally, 36 metabolites were causally related to HCC. Based on known causal metabolites, we observed that the glycerophospholipid metabolism pathway is closely related to HCC. Utilizing two-step MR analysis, 11 cell phenotypes were determined to have causal relationships with HCC mediated by 14 plasma metabolites, with Linolenate [alpha or gamma; (18:3n3 or 6)] levels showing the highest mediation proportion (19.3%). Conclusion Our findings affirm a causal relationship between immune cell phenotypes, plasma metabolites, and HCC, computing the proportion of the effect mediated by plasma metabolites. This study provides novel insights into the prevention, diagnosis, and treatment of HCC.