Trans-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density lipoprotein-cholesterol lowering and gallstone disease

Structured abstractO_ST_ABSBackgroundC_ST_ABSPlasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. ObjectivesWe tested the hypothesis that different plasma LDL-cholesterol lowering pathways have distinct effects on biliary cholesterol and thereby risk of gallstone disease. MethodsThis Mendelian randomization (MR) study used data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). First, drug-target MR and colocalization analyses were performed to investigate plasma LDL-cholesterol lowering therapies on gallstone disease. Second, clustered MR and pathway analyses were performed to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease. ResultsFor a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower risk of gallstone disease (odds ratio 0.72 [95% confidence interval 0.62, 0.83]) but PCSK9 inhibitors and mipomersen were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease, with evidence for ancestry-and sex-specific associations. Among variants predicting lower plasma LDL-cholesterol, those associated with lower risk of gallstone disease were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters. ConclusionsDifferent plasma LDL-cholesterol lowering pathways may have opposing effects on risk of gallstone disease. Notably, statins may reduce risk of gallstone disease. Condensed abstractWe hypothesized that different plasma LDL-cholesterol lowering pathways have distinct effects on risk of gallstone disease. We performed drug-target and clustered Mendelian randomization (MR) analyses, using data from the UK Biobank, FinnGen and Biobank Japan. Genetic mimics of statins were associated with lower risk of gallstone disease, but PCSK9 inhibitors and mipomersen were associated with higher risk. Clustered MR identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease. This genetic study supports that different plasma LDL-cholesterol lowering pathways have opposing effects on risk of gallstone disease and statins may reduce risk of gallstone disease.