Genetically predicted blood metabolites mediate the association between circulating inflammation-related proteins and pancreatic cancer

Background : While extensive research highlighted the involvement of circulating inflammatory proteins and metabolism in pancreatic cancer (PC), causality remains unestablished. In the present study, we aimed to investigate the causal relationship of circulating inflammatory proteins and pancreatic cancer and identify the blood metabolites as potential mediators. Methods : We employed bidirectional two-sample Mendelian randomization analysis to examine the potential causal association between circulating inflammatory proteins, circulating metabolites, and PC using data from genome-wide association studies (GWAS). And two-step MR to discover potential mediating blood metabolites in this process. Results : MR analysis identified 4 types of circulating inflammation-related proteins causally associated with pancreatic cancer. Furthermore, there was no strong evidence that genetically predicted pancreatic cancer had an effect on these four types of circulating inflammatory proteins. Further two-step MR analysis found 11 types of blood metabolites were causally associated with pancreatic cancer and the associations between circulating Interleukin-15 receptor subunit alpha and pancreatic cancer were mediated by blood 5-methyluridine with proportions of 7.41%. Conclusion : The present study provides evidence supporting the causal relationships between various circulating inflammatory proteins, especially Interleukin-15 receptor subunit alpha, and pancreatic cancer, with a potential effect mediated by blood metabolites. Further research is needed on additional risk factors as potential mediators and establish a comprehensive inflammation-metabolism network in pancreatic cancer.