Exploring causal relationship between the lipids, immune cells, and leiomyosarcoma: A Mendelian randomization and mediation analysis

This study aimed to delineate the causal nexus between lipids and leiomyosarcoma (LMS), with a particular emphasis on delineating the mediating role of immune cells. Employing a 2-sample Mendelian randomization (MR) framework, we scrutinized the potential association of 179 lipid species with LMS across 179 cases and 314,193 controls. The analysis was underpinned by summary-level data derived from genome-wide association studies. The inverse variance weighting method constituted our primary analytical strategy, augmented by supplementary techniques including MR-Egger, simple mode, weighted median, and weighted mode. To ensure the integrity of our MR inferences, we conducted rigorous horizontal multiplicity, heterogeneity, and Bayesian assessments. Furthermore, a nuanced 2-step Mendelian analysis was undertaken to quantify the extent of immune cell-mediated effects of lipids on LMS. Our comprehensive MR evaluation of 179 lipids species unveiled a significant association between genetically inferred triglyceride levels and an elevated risk of LMS (odds ratio = 2.11, 95% confidence interval = 1.38-3.23, P < .001), while inversely showing no effect of LMS on triglyceride levels (odds ratio= 0.99, 95% confidence interval = 0.94-1.04, P = .83). Additionally, the examination of 731 immune cell phenotypes highlighted CD8+ natural killer T cells as contributing a 6% mediation in the causal pathway from triglycerides to LMS.