Causal relationships between immunophenotypes, plasma metabolites, and pancreatic cancer: a mediation Mendelian randomization study

Background: Current research exploring the interconnections between Immune cell phenotype, plasma metabolites, and the risk of pancreatic cancer remains scant. Further investigation is necessary to understand the complex interactions involved. Methods: Instrumental variables for 731 immune phenotypes (N = 3,757), 1,400 circulating metabolites (N = 8,299), and pancreatic cancer (N = 1,196) were obtained from a meta-analysis of genome-wide association studies (GWAS). A two-step, two-sample Mendelian randomization study using the IVW method was conducted to investigate the causal influence of immune cell phenotypes on pancreatic cancer and to assess the intermediary role of circulating metabolites within this context. Sensitivity analyses were performed to test the robustness of the results, potential heterogeneity, and pleiotropy. Results: Mendelian randomization analyses identified protective effects of CD64 on monocyte (OR = 0.859, 95% CI 0.802-0.920, P = 1.65 × 10 , P = 0.012) against pancreatic cancer. Additionally, 68 metabolites were suggestively associated with pancreatic cancer. Notably, mediation MR revealed that the causal role of CD64 on monocytes in pancreatic cancer was largely mediated by 1-palmitoleoylglycerol (16:1) level (OR = 0.0089, 95% CI 0.00121-0.0167, P = 0.023), accounting for 5.91% of the total effect. Conclusion: There is a causal relationship between CD64 on monocytes and pancreatic cancer, which may be related to mediation by circulating metabolites. This study enhances our understanding of the interplay between immune responses and the risk of pancreatic cancer, offering valuable insights for the development of immune-oriented therapeutic strategies.