Genetically Predicted 12,13-DiHOME Mediates theAssociation between TNF-Related ApoptosisInducing Ligand and Immune Thrombocytopenia

Introduction: The role of Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) has been highlighted in autoimmune and metabolic disorders. However, there is still an inadequate explanation of its causal relationship with primary immune thrombocytopenia (ITP). This study employed Mendelian Randomization (MR) to identify the potential causal associations among TRAIL, plasma metabolites, and ITP. Method: This study was conducted focusing on analyzing data from a Genome-Wide Association Study (GWAS) comprising inflammatory proteins, plasma metabolites, and the FinnGen consortium. The Inverse Variance Weighted (IVW) method was adopted to derive the causal estimates primarily. Sensitivity analyses included Cochran’s Q test for heterogeneity, MR-Egger regression for horizontal pleiotropy, leave-one-out analysis, and validation via Bayesian Weighted MR (BWMR). In addition, the identification and quantification of potential mediating metabolites were realized through a two-step MR approach. Results: Genetically predicted higher TRAIL levels were associated with a reduced risk of ITP (IVW odds ratio [OR] = 0.78, 95% confidence interval [CI]: 0.65–0.92, P = 0.0042), which was confirmed by BWMR (OR = 0.77, 95% CI: 0.65–0.92, P = 0.0043). Reverse MR analysis revealed no significant causal effect of ITP on TRAIL. Among the 48 plasma metabolites causally associated with TRAIL, only 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME) exhibited a significant association with ITP in BWMR (OR = 0.75, 95% CI: 0.58–0.97, P = 0.0316). Mediation analysis suggested that 12,13-DiHOME might partially mediate the effect of TRAIL on ITP, with an exploratory estimated mediation proportion of 7.55%. Discussion: Mediation analysis revealed that 12,13-DiHOME mediated 7.55% of the TRAIL-related ITP risk reduction. These findings provide preliminary evidence supporting a potential mediating role of 12,13-DiHOME in the protective effect of TRAIL against ITP, suggesting the existence of an immunometabolic pathway linking TRAIL to ITP pathogenesis. Conclusion: This MR study provides genetic evidence of the potentially protective causal effect of TRAIL against ITP, which may be mediated partially by 12,13-DiHOME. Our findings may highlight a novel immunometabolic pathway in ITP pathogenesis, meriting further investigation