The role of gallstones in gallbladder cancer in India: A mendelian randomization study

Background: Past history of gallstones is associated with increased risk of gallbladder cancer in observational studies. We conducted complementary observational and Mendelian randomization (MR) analyses to determine whether history of gallstones is causally related to development of gallbladder cancer in an Indian population. Methods: To investigate associations between history of gallstones and gallbladder cancer, we used questionnaire and imaging data from a gallbladder cancer case-control study conducted at Tata Memorial Hospital, Mumbai, Maharashtra, India (cases ¼ 1,170; controls ¼ 2,525). We then used 26 genetic variants identified in a genome-wide association study of 27,174 gallstone cases and 736,838 controls of European ancestry in an MR approach to assess causality. The association of these genetic variants with both gallstones and gallbladder cancer was examined in the gallbladder cancer case-control study. Various complementary MR approaches were used to evaluate the robustness of our results in the presence of pleiotropy and heterogeneity, and to consider the suitability of the selected SNPs as genetic instruments for gallstones in an Indian population. Results: We found a strong observational association between gallstones and gallbladder cancer using self-reported history of gallstones [OR ¼ 4.5; 95% confidence interval (CI) ¼ 3.5-5.8] and with objective measures of gallstone presence using imaging techniques (OR ¼ 2.0; 95% CI ¼ 1.5-2.7). We found consistent causal estimates across all MR techniques, with ORs for gallbladder cancer in the range of 1.3-1.6. Conclusions: Our findings indicate a causal relationship between history of gallstones and increased risk of gallbladder cancer, albeit of a smaller magnitude than those found in observational analysis. Impact: Our findings emphasize the importance of gallstone treatment for preventing gallbladder cancer in high-risk individuals.