Metabolomic profiles of incident gallstone disease

Background and aims: Gallstone disease affects >= 40 million people in the USA and accounts for health costs of >=$4 billion a year. Risk factors such as obesity and metabolic syndrome are well established. However, data are limited on relevant metabolomic alterations that could offer mechanistic and predictive insights into gallstone disease. This study prospectively identifies and externally validates circulating prediagnostic metabolites associated with incident gallstone disease. Methods: Female participants in Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) who were free of known gallstones (N=9960) were prospectively followed up after baseline metabolomic profiling with liquid chromatography-tandem mass spectrometry. Multivariable logistic regression and enrichment analysis were used to identify metabolites and metabolite groups associated with incident gallstone disease at P-FDR<0.05. Findings were validated in 1866 female participants in the Women's Health Initiative and a comparative analysis was performed with 2178 male participants in the Health Professionals Follow-up Study. Results: After multivariate adjustment for lifestyle and putative risk factors, we identified and externally validated 17 metabolites associated with incident gallstone disease in women-nine triacylglycerols (TAGs) and diacylglycerols (DAGs) were positively associated, while eight plasmalogens and cholesterol ester (CE) were negatively associated. Enrichment analysis in male and female cohorts revealed positive class associations with DAGs, TAGs (<= 56 carbon atoms and <= 3 double bonds) and de novo TAG biosynthesis pathways, as well as inverse associations with CEs. Conclusions: This study highlights several metabolites (TAGs, DAGs, plasmalogens and CE) that could be implicated in the aetiopathogenesis of gallstone disease and serve as clinically relevant markers.