Mendelian randomisation study of the effects of known and putative risk factors on pancreatic cancer

BACKGROUND: Observational studies have reported multiple risk factors for pancreatic ductal adenocarcinoma (PDAC). Some are well established, like tobacco smoking, alcohol drinking, obesity and type 2 diabetes, whereas some others are putative, such as allergy and dietary factors. Identifying causal risk factors can help establishing those that can be targeted to contribute to prevent PDAC. OBJECTIVE: We sought to investigate the possible causal effects of established and putative factors on PDAC risk. METHODS: We conducted a two-sample Mendelian randomisation (MR) study using publicly available data for genetic variants associated with the factors of interest, and summary genetic data from genome-wide association studies of the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including in total 8769 cases and 7055 controls. Causality was assessed using inverse-variance weighted, MR-Egger regression and weighted median methods, complemented with sensitivity and radial MR analyses. Fasting insulin (OR 2.84, 95% CI 1.23 to 6.56, p=0.01), low-density lipoprotein cholesterol (OR 1.16, 95% CI 1.02 to 1.32, p=0.03) and type 2 diabetes (OR 1.09, 95% CI 1.01 to 1.17, p=0.02) were also causally associated with PDAC risk. BMI showed both direct and fasting insulin-mediated causal effects. CONCLUSION: We found strong evidence that BMI is causally associated with PDAC risk, providing support that obesity management may be a potential prevention strategy for reducing pancreatic cancer risk while fasting insulin and type 2 diabetes showed a suggestive association that should be further investigated.