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

Abstract

Introduction: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Autoimmune diseases; Biliary tract cancer; Causal relationship; Interleukin-1; Ulcerative colitis.

Graphical abstract

Fig. 1

Diagram of meta-analysis and Mendelian randomization framework in this study.

Fig. 2

The causal associations between GSD, GIs and common inflammatory diseases of the digestive system, and the risk of biliary tract cancer using univariable Mendelian-randomization (GSD: gallstone disease, PSC: primary sclerosing cholangitis, PBC: primary biliary cholangitis, IBD: inflammatory bowel disease, UC: ulcerative colitis, CD: Crohn's disease, IBS: irritable bowel syndrome, PUD: peptic ulcer disease, GERD: gastro­esophageal reflux disease).

Fig. 3

The independent effect of these genetic risk factors of biliary tract cancer adjusted by one and more confounders using multivariable Mendelian-randomization (Al. the effect of GSD on BTC risk, A2. the effect of cholecystitis on BTC risk, A3. the effect of gallbladder polyps on BTC risk, A4. the effect of PSC on BTC risk, and A5. the effect of UC on BTC risk; Color note. Orange: Only one factor adjusted, Green: Two factors adjusted, Blue: Three factors adjusted, and Purple: Four factors adjusted). Bl & B2. The risk of BTC with the different models including GIs. C. The genetic correlation-analysis between GI and BTC. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

A-D: Analysis of bidirectional-MR and mediation-effect for the associations between the significant causal factors and the risk of biliary tract cancer; E: The network relationships of early-onset biliary tract cancer risk with the directly genetic factors. The dashed red line means that these factors are significantly associated with BTC in UVMR; the solid red line means that this factor may be an independent risk factor for BTC after adjusting for confounding by MVMR analysis; while the solid black line indicates the causal correlation between factors other than BTC. Note: GSD, gallstone disease; CHO, cholecystitis; GBP, gallbladder polyp; PSC, primary sclerosing cholangitis; UC, ulcerative colitis. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)