Genetic susceptibility to nonalcoholic fatty liver disease and risk for pancreatic cancer:Mendelian randomization

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer (PC). Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for PC. METHODS: Data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium (PanScan; cases n=5090, controls n=8733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n=4,163, controls n=3,792) were analyzed. We used data on 68 genetic variants with four different MR methods (inverse variance weighting [IVW], MR-Egger, simple median, and penalized weighted median) separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and PC risk, using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and PC risk in the PanScan or PanC4 samples (e.g., PanScan, IVW OR=1.04, 95% CI: 0.88-1.22, MR-Egger OR=0.89, 95% CI: 0.65-1.21; PanC4, IVW OR=1.07, 95% CI: 0.90-1.27, MR-Egger OR=0.93, 95% CI: 0.67-1.28). None of the four MR methods indicated an association between genetically predicted NAFLD and PC risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with PC risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and PC might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and PC