Causal effects of cholecystectomy on the lipidome: cross-sectional and mendelian randomization studies.

Background: Cholecystectomy, the surgical removal of the gallbladder, is a widely performed procedure. The gallbladder plays an important role in lipid metabolism, but the effects of its removal on lipidome remains unexplored.

Methods: This study evaluated the association of cholecystectomy with lipid profiles in two phases. First, a cross-sectional analysis of National Health and Nutrition Examination Survey (NHANES) data employed multivariate linear regression with propensity score matching to compare lipid profiles, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), between individuals with and without a history of cholecystectomy. Second, Mendelian randomization analysis leveraged large-scale GWAS datasets (GWAS Catalog, IEU OpenGWAS, Global Lipids Genetics Consortium) to evaluate causal effects on TC, LDL-C, HDL-C, TG, and 106 lipid-related phenotypes across multicenter cohorts.

Results: NHANES analysis revealed a significant association between cholecystectomy and lower levels of TC (β = - 0.23, 95% CI: - 0.40 to - 0.07, p = 0.009) and LDL-C (β = - 0.30, 95% CI: - 0.46 to - 0.13, p = 0.002), with no significant associations observed for HDL-C or TG. Mendelian randomization analysis further confirmed a causal relationship between cholecystectomy and lower levels of in TC, LDL-C, and 21 related lipid metabolites-including free cholesterol, apolipoprotein B, 14 low-density lipoprotein related metabolites, and 5 intermediate-density lipoprotein related metabolites-all integral to TC and LDL-C metabolism. No causal effects were identified for HDL-C, TG, or their corresponding lipid subtypes.

Conclusions: Cholecystectomy is robustly associated with lower levels of TC, LDL-C, and 21 related lipid metabolites, with no significant associations observed for TG, HDL-C, or their subtypes. These findings enhance our understanding of the metabolic associations of gallbladder removal and suggest potential cardiovascular benefits.