Peripheral white blood cell counts and pancreatic cancer risk: a Mendelian randomization study

Abstract:

Background and Aims Pancreatic cancer has an extremely poor prognosis, and effective screening strategies for the general population are lacking. Circulating white blood cells are accessible immunoinflammatory markers, but their causal relationship with pancreatic cancer risk remains unclear. This study aimed to systematically evaluate the potential causal associations between peripheral white blood cell counts and pancreatic cancer risk using Mendelian randomization (MR).Methods A two-sample MR design was applied. GWAS summary statistics for total white blood cell count and five major subtypes were obtained from the Blood Cell Consortium. Pancreatic cancer outcome data were derived from FinnGen release 12 (European population), with additional validation using East Asian GWAS datasets. The inverse-variance weighted (IVW) method was used as the primary analysis, complemented by multivariable MR, reverse MR, and multiple sensitivity analyses.Results Univariable MR analysis showed that genetically predicted higher eosinophil count was associated with a lower risk of pancreatic cancer (IVW: OR=0.886, 95% CI=0.793-0.990, P=0.033), with consistent direction across methods. Multivariable MR confirmed that this protective association persisted after adjusting for other leukocyte subtypes (OR=0.848, 95% CI=0.723-0.995, P=0.043). Reverse MR provided no evidence for a causal effect of pancreatic cancer on white blood cell traits. The East Asian validation analysis showed a consistent direction of effect. No robust associations were observed for other leukocyte traits.Conclusion Genetically predicted higher eosinophil levels may be associated with a reduced risk of pancreatic cancer. These findings provide supportive evidence for the immunoetiology of pancreatic cancer, but are not yet sufficient for direct clinical application.