Unveiling the association between plasma lipid species and pan-cancers: A bidirectional 2-sample Mendelian...

Plasma lipids play a crucial role at every stage of cancer progression, and a deficiency or excess of plasma lipids can lead to an increased risk of cancer. Previous observational studies and randomized controlled trials on the association between plasma lipids and cancer risk have been limited. We conducted a Mendelian randomization (MR) analysis to assess the impact of 179 plasma lipid species on the risk of 15 types of cancer. Through bidirectional 2-sample MR analysis and colocalization analysis, we systematically studied the association between 179 plasma lipid species and 15 types of cancer. In the MR study, we primarily used inverse variance weighting as our analytical strategy. Sensitivity analyses were carried out using the MR-Egger method and the MR Pleiotropy Residual Sum and Outlier method. We rigorously assessed heterogeneity through the application of Cochrane Q test. To ensure the robustness of the MR results, we employed the "leave-one-out" method and tested the strength of the causal relationships through false discovery rate correction. We identified a significant causal relationship between 20 plasma lipid species and the risk of 5 types of cancer. Specifically, in the forward MR analysis, the level of plasma phosphatidylethanolamine (18:0_20:4) was causally linked with pancreatic cancer; the level of plasma phosphatidylcholine (O-18:0_16:1) was causally linked with breast cancer (estrogen receptor [ER]+); the level of plasma phosphatidylcholine (O-16:0_20:3) was causally linked with endometrial cancer (endometrioid histology); 3 plasma lipid species were causally linked with lung cancer; and 14 plasma lipid species were causally linked with colorectal cancer. Strong evidence from colocalization analysis confirmed that 11 plasma lipid species shared causal variants with the risk of colorectal cancer. In the reverse analysis, an increased risk of colorectal cancer was associated with elevated levels of plasma phosphatidylcholine (18:1_18:2). This discovery held strong in comprehensive sensitivity analyses. We did not find a clear link between other plasma lipids and cancer. Our research results powerfully demonstrated the role of plasma lipids in cancer risk.