Immune cells as mediators in lipids-colorectal cancer risk: A Mendelian randomization study

The occurrence and progression of colorectal cancer (CRC) are closely associated with abnormal lipid metabolism and immune regulation in the tumor microenvironment. Lipids are not only essential components of cell membranes but also influence CRC progression by modulating signaling pathways and inflammatory responses. In recent years, Mendelian randomization (MR) analysis, a causal inference method utilizing genetic variants as instrumental variables, has provided a novel approach to investigate the relationship between lipids and CRC risk. Immune cells in the CRC microenvironment play a dual role, either promoting antitumor immunity or accelerating tumor immune escape. However, how lipids mediate this causal pathway through immune cells remains unclear. This study aims to investigate the impact of the lipids on CRC risk and determine the potential involvement of immune cells as mediators. Utilizing single nucleotide polymorphisms as instrumental variables, a 2-sample bidirectional MR was conducted to explore the potential causal relationship between lipids and CRC. Subsequently, A 2-step MR analysis was implemented to determine the effect value of immune cell features as mediators. Heterogeneity was assessed using the Cochran Q test. MR-Egger intercept and MR-Pleiotropy RESidual Sum and Outlier Global Test were employed for evaluation pleiotropy. Excluding a lipid with reverse causal effects, 5 lipids were demonstrated to exert causal effects on CRC risk, including phosphatidylcholine (20:4_0:0), phosphatidylethanolamine (O-18:2:20:4), sphingomyelin (d38:1), sphingomyelin (d 40:2), triacylglycerol (49:2). CD80 on CD62L+ myeloid DC (mediator effect β = -0.0050), CD45 on CD33br HLA DR+ (mediator effect β = -0.0041) and Basophil %CD33dim HLA DR- CD66b- (mediator effect β = -0.0145) were involved as mediating factors. The results of our study indicated causal connections between CRC risk and multiple lipids with immune cells involved as mediators.