Gastrointestinal traits, common inflammatory disorders, gallstones, and biliary tract cancer: A network Mendelian randomization study

Observational studies have shown that gallstone disease (GSD), cholecystitis, cholangitis, polyp of gallbladder, viral hepatitis, pancreatitis and gastrointestinal (GI) traits such as H. pylori infection, inflammatory bowel disease, and digestive ulcer are associated with the risk of biliary tract cancer (BTC). However, no study has explored their causal associations. To gain a more comprehensive understanding of the causal relationships between GI traits, inflammatory diseases of the digestive system, gallstones, and the development of BTC, further investigation into a comprehensive causal network is warranted. Based on findings of our Meta-analysis, the present study proposed to investigate the causal role of GSD (26,122 recorded cases) together with 15 GIs and common digestive system inflammatory diseases (sample size from 14,890 to 602,604) in the risk of incident BTC (832 cases and 475,259 controls), using a network Mendelian randomization. Independent associations were further discovered. We found significant positive associations between GSD (OR = 1.26, 95 %CI: 1.05-1.51), cholecystitis (OR = 1.43, 95 %CI: 1.20-1.69), gallbladder polyps (OR = 1.11, 95 %CI: 1.00-1.24), primary sclerosing cholangitis (PSC, OR = 1.07, 95 %CI: 1.00-1.13), ulcerative colitis (UC, OR = 1.07, 95 %CI: 1.00-1.14) and the risk of BTC. The association of GSD with BTC was attenuated after adjusting for cholecystitis and gallbladder polyps (OR = 1.45, 95 %CI: 0.60-3.52), while the association of UC remained significant, without the mediation of biliary tract diseases (OR = 1.12, 95 %CI: 1.03-1.22). Beyond that, we verified that the causal associations between primary biliary cholangitis, viral hepatitis, chronic pancreatitis, gastritis, gastric ulcer, Crohn's disease, irritable bowel syndrome, peptic ulcer disease, gastroesophageal reflux disease, appendicitis, and an increased risk of BTC were not significant. Our results implicate the effect of GSD on incident BTC to interact with cholecystitis and polyp of gallbladder, while UC as an independent risk factor for BTC. Clinical studies are needed to determine our findings.