Causal relationship between serum bilirubin, cholelithiasis and hepatobiliary and pancreatic malignancy: A bidirectional and 2-sample Mendelian randomization study

Since the causal relationship between cholelithiasis and serum bilirubin levels and hepatobiliary and pancreatic malignancies has been inconclusive and inconsistent for a long time, to control confounding factors and reverse causality as much as possible, this paper adopted a Mendelian randomization (MR) study to reveal further the causal relationship between different exposure factors and hepatobiliary and pancreatic malignancies. This study selected 4 exposure factors, including cholelithiasis, serum total bilirubin, direct bilirubin, and indirect bilirubin, by double-sample and bidirectional MR method. The results were as follows: gallbladder carcinoma, liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PADC) were selected as the outcome, and significance level (P < 5e-08) was used as the filtering criterion to select genetic variation as the instrumental variable for follow-up analysis. Then, we calculated the odds ratio between exposure and outcome to show the causal relationship between different exposure factors and outcome. A series of sensitivity analyses were conducted to verify the conclusions' reliability. There was a causal relationship between direct bilirubin and gallbladder cancer, and direct bilirubin was a risk factor for gallbladder cancer (odds ratio = 3.07, 95% confidence interval = 1.02-9.22, P = .04). We then performed a reverse MR analysis on this analysis to further analyze the possible reverse causality between the 2 and found no reverse causality between the 2 (P = .22). At the same time, other exposure factors in the study did not show a causal relationship with the outcome. This study showed that serum direct bilirubin is a risk factor for gallbladder cancer. The conclusion was statistically significant (P = .04), and reverse MR excluded the reverse causal association between the 2. Cholelithiasis, serum total bilirubin, and indirect bilirubin were not causally associated with gallbladder cancer, and none of the exposure factors in the study showed a causal association with hepatocellular carcinoma and pancreatic cancer.