PPP1R3B rs4240624 genotype is associated with gallstones and with significant changes in bile lipidome

Background and Aims Gallstone disease associates with significant morbidity and mortality. Decreased secretion of bile acids has been suggested as a driving factor for gallstone disease. Recently, we linked the PPP1R3B rs4240624 genotype to decreased bile acid levels in bile. In this study, we investigated whether these individuals had an increased risk for gallstone disease as well as the differences in the lipid composition of the gallbladder bile of these individuals compared to controls and patients with gallstone disease. Methods Bile acids, cholesterol, and phospholipid levels in gallbladder bile samples were enzymatically measured in 46 patients (34 female, age 45.7±9.8 years, BMI 41.3±4.4 kg/m2) who underwent elective laparoscopic Roux-en-Y gastric bypass. The lipidome of gallbladder bile was analyzed using high-performance liquid chromatography-mass spectrometry. Gallstone status was evaluated using abdominal ultrasonography before the surgery. Results The G allele of PPP1R3B rs4240624 was significantly associated with gallstone disease in patients with obesity. We validated this association in the UK Biobank. Bile lipidomics demonstrated that 13 of the 17 minor lipid classes measured were higher in individuals with the G allele. The concentrations of bile acids, cholesterol, and phospholipids, as well as the cholesterol saturation index, were lower in patients with gallstone disease than in those without gallstones. Gallstone disease had an effect similar to that of PPP1R3B genotype on minor lipids. Conclusions The PPP1R3B rs4240624 genotype is associated with gallstones and with changes in gallbladder bile similar to those observed in patients with gallstones, suggesting that the PPP1R3B genotype contributes to the risk of gallstones by altering the bile lipidome.