Indirect Roles of Immunophenotypes in the Association Between Glycerophospholipid Metabolism and Endometrial Cancer Risk: A Mendelian Randomization Study

Background: The incidence of endometrial cancer (EC) has continued to rise in recent years. Increasing evidence suggests that lipid metabolic alterations in serum metabolites are associated with cancer progression. Methods: This research applied a two-step Mendelian Randomization (MR), two-sample MR methodology to explore the potential causal associations between glycerophospholipid metabolism and EC risk, as well as possible indirect roles of immunophenotypes, drawing data from the Genome-Wide Association Study Catalog and EC Association Consortium databases. The Inverse Variance Weighted, MR-Egger regression, Weighted Median Estimator, Simple Mode, and Weighted Mode approaches formed a comprehensive array of MR methodologies predominantly employed to assess causality. Several sensitivity analyses were implemented to verify the reliability of MR results. Results: Genetically predicted levels of three metabolites were associated with EC risk, with evidence suggesting partially indirect pathways involving four immunophenotypes. 1-(1-enyl-palmitoyl)-GPC (p-16:0) was found to diminish EC risk, potentially through indirect pathways involving, specifically CD33dim HLA-DR+ CD11b- AC, and CD25 on memory B cells, explaining 3.99% and 5.68% to the total effect, respectively. Additionally, 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1) decreased EC risk, with partial mediation by B cell % CD3- lymphocyte, accounting for a 3.25% share of the indirect effect. Conversely, Eicosenedioate (C20:1-DC) increased EC risk, with its effect being mediated by CD38 on PB/PC cells, exerting a indirect effect of up to 10.09%. Conclusion: This investigation provides genetic evidence supporting potential causal associations between glycerophospholipid metabolism and EC, highlighting possible indirect pathways of immunophenotypes. The derived insights offer novel pathways for the diagnosis and therapeutic intervention of EC.