Gallstones: a driver of cardiovascular disease? A triangulation study

<jats:sec> <jats:title>Objective</jats:title> <jats:p>Gallstone carriers have elevated cardiovascular disease (CVD) risk. Shared lifestyle risk factors only partly explain the observed association. Gallstone-driven inflammation may contribute to CVD with cholecystectomy offering protection. A triangulation study using observational, genetic and interventional data was undertaken.</jats:p> </jats:sec> <jats:sec> <jats:title>Design</jats:title> <jats:p>Cox proportional hazards analysis of UK Biobank data assessed 10-year CVD risk in gallstone cases versus healthy controls and gallstone carriers versus post-cholecystectomy individuals. Data were meta-analysed with other published cohorts. Gallstone state was additionally modelled as a time-varying covariate with states: gallstone-free, gallstone-carrier, gallstone-related inflammation and post cholecystectomy. Finally, Mendelian randomisation (MR) analyses were undertaken using 41 gallstone-promoting single nucleotide polymorphisms (SNPs) to assess causal effects of gallstones on CVD.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>In UK Biobank (gallstones=32,528, controls=424,520) and meta-analysis (gallstones=202,055, controls=1,256,861), gallstones were associated with CVD (adjusted HR (aHR) 1·28 (1·20 to 1·36), meta-analysis aHR 1·23 (1·18 to 1·29)). Cholecystectomy was associated with reduced CVD risk compared with gallstone carriers (aHR 0·71 (0·62 to 0·82)). Time-varying analysis supported elevated CVD risk with inflammation and reduced CVD following cholecystectomy. MR analyses required handling of pleiotropic cholesterol-lowering SNPs that affect CVD risk independently of gallstones. Multivariable MR adjusting for the impact of SNPs on lipids showed no significant association of CVD and gallstones.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Gallstones are associated with elevated CVD risk, which increased with gallstone-related inflammation but diminished post cholecystectomy. The benefits of cholecystectomy indicate a potential causal pathway. However, as cholecystectomy interrupts exposure to gallstones, the effects of gallstone-promoting SNPs on CVD are likely attenuated by cholecystectomy, meaning MR analyses cannot detect an underlying causal effect.</jats:p> </jats:sec>