J Leukoc Biol. 2025 Aug 14:qiaf120. doi: 10.1093/jleuko/qiaf120. Online ahead of print.
ABSTRACT
Existing studies examining the relationships among immunological cell phenotype, plasma metabolites, and pancreatic cancer susceptibility are limited. More comprehensive research is required to elucidate the complex interactions underlying these associations. Genetic instruments for 731 immune phenotypes (N = 3,757), 1,400 circulating metabolites (N = 8,299), and pancreatic cancer (N = 1,196) were derived from a genome-wide association studies (GWAS) meta-analysis. A two-step, two-sample Mendelian randomization (MR) 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. Sensitivity analyses were carried out to verify the robustness, potential heterogeneity, and pleiotropy. MR analyses identified protective effects of CD64 on monocyte (OR = 0.859, 95%CI 0.802-0.920, P = 1.65 × 10-5, PBonferroni = 0.012) against pancreatic cancer. Moreover, 68 metabolites were suggestively associated with pancreatic cancer. Notably, mediation MR revealed that the causal role of CD64 on monocyte 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. These findings establish a causal relationship between CD64 on monocytes and pancreatic cancer, possibly operating through circulating metabolites. The research advances knowledge of the interplay between immune responses and the risk of pancreatic cancer, providing important implications for immunologically targeted treatment approaches.
PMID:40811672 | DOI:10.1093/jleuko/qiaf120