Immune Cell-Mediated Effect of Lipid Profile on Colorectal Cancer: A Two-Step, Two-Sample Mendelian Randomization Study

ObjectiveTo elucidate the bidirectional causal relationship between lipid profiles and colorectal cancer (CRC) by using the two-sample and two-step Mendelian randomization (MR) methods, and to explore the mediating role and proportion of immune cells as intermediary factors. MethodsThe pooled statistical data related to the study were screened, and 179 lipids and CRC were analyzed using two-sample and two-step MR with the inverse variance weighted method. Simultaneously, the causal effect was verified via Bayesian weighted MR. Two-step MR analysis was conducted to determine whether a mediated effect was exerted on immune cell traits. Sensitivity, heterogeneity, and pleiotropy analyses were performed to verify the reliability of the study results. ResultsThe causal relationship between nine lipid traits and CRC was preliminarily identified, and no reverse causal effect was found (P>0.05). The validity of the results was verified via Bayesian weighted MR (P<0.05). Twenty-seven types of immune cells were suggested to exert a causal effect on CRC. The causal effect of phosphatidylcholine (O-18:2_20:4) on CRC was determined via mediation analysis (OR: 0.8579, 95%CI=0.7395-0.9952, P=0.0429). The CD127-mediated proportion on CD45RA+ CD4+ T cells was 9.14% (β=−0.1052, P=0.0155). ConclusionA causal relationship exists between lipid traits and CRC, and the intervention of CD127 on CD45RA+ CD4+ T cell helps phosphatidylcholine reduce the risk of CRC.