Cholecystitis and cholangiocarcinoma: a two-sample Mendelian randomization study

Over the past few decades, the global incidence of cholangiocarcinoma has risen overall. In particular, the incidence of intrahepatic cholangiocarcinoma increased by 109% over a ten-year period, rising from 0.67 per 100,000 in 2007 to 1.40 per 100,000 in 2016¹. Epidemiological studies have suggested that cholecystitis may increase the risk of hepatobiliary cancers. However, whether this association indicates an independent causal relationship remains unclear. Given that observational studies are prone to residual confounding and bias, limiting the strength of causal inference. Our study aimed to evaluate whether cholecystitis is an independent risk factor for cholangiocarcinoma.

Instrumental variables were identified as independent single nucleotide polymorphisms highly associated with cholecystitis (n = 25). The entire dataset from the Integrative Epidemiology Unit (IEU) publicly available genome-wide association studies (GWAS) was utilized to obtain cholangiocarcinoma outcome data (n = 25). In this study, five MR statistical techniques (Inverse Variance Weighted, MR Egger, Weighted Median, Simple Mode, and Weighted mode) were used. The MR Egger intercept test, leave-one-out analysis, and the funnel plot were all utilized in sensitivity analyses.

Results of the Inverse Variance Weighted (IVW) method genetically predicted cholecystitis was associated with higher risk of cholangiocarcinoma, with an odds ratio of 2.915 (95% CI = 1.122-7.575, P = 0.038). Weighted Median Method also demonstrated consistent direction of effect (P = 0.016). However, MR-Egger, Simple Mode, and Weighted Mode all showed no statistical significance (P > 0.05). Both funnel plots and MR Egger intercepts indicated the absence of any directional pleiotropic effects between cholecystitis and cholangiocarcinoma.

We found evidence supporting a causal effect between cholecystitis and cholangiocarcinoma, indicating an increased likelihood of cholangiocarcinoma in patients with cholecystitis through MR analysis.These findings may help inform clinical strategies for the management of cholecystitis, with the aim of potentially reducing the risk of cholangiocarcinoma.