Plasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. Different plasma LDL-cholesterol lowering pathways may have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using 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). We first performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone disease risk. We then performed clustered MR analyses and pathway analyses to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease risk. For a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower gallstone disease risk (odds ratio 0.72 [95% confidence interval 0.62, 0.83]), but genetic mimics of PCSK9 inhibitors and targeting apolipoprotein B 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 risk, with some evidence for ancestry-and sex-specific associations. Among variants lowering plasma LDL-cholesterol, those associated with lower gallstone disease risk 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. This MR study provides genetic evidence that different plasma LDL-cholesterol lowering pathways have opposing effects on gallstone disease risk.

血浆低密度脂蛋白 （LDL） 胆固醇与冠状动脉疾病风险呈正相关，而胆汁胆固醇促进胆结石形成。不同的血浆 LDL-胆固醇降低途径可能对胆汁胆固醇产生不同的影响，从而对胆结石疾病风险产生影响。我们使用来自英国生物样本库 （30,547 例胆结石病病例/336,742 例对照）、FinnGen （34,461 例/301,383 例对照） 和日本生物样本库 （9,305 例/168,253 例对照） 的数据进行了一项孟德尔随机化 （MR） 研究。我们首先进行了通过共定位证实的药物靶点 MR 分析，以研究血浆 LDL-胆固醇降低疗法对胆结石疾病风险的影响。然后，我们进行了聚类 MR 分析和通路分析，以确定血浆 LDL-C 与胆结石疾病风险相关的不同机制。血浆 LDL-胆固醇降低 1 个标准差时，他汀类药物的遗传模拟物与较低的胆结石病风险相关 （比值比 0.72 [95% 置信区间 0.62， 0.83]），但 PCSK9 抑制剂的遗传模拟物和靶向载脂蛋白 B 与较高的风险相关 （1.11 [1.03， 1.19] 和 1.23 [1.13， 1.35]）。共定位支持他汀类药物的关联 （后验概率 98.7%）。聚类 MR 分析确定了显示血浆 LDL-胆固醇与胆结石病风险相反关联的变异簇，并有一些证据表明血统和性别特异性关联。 在降低血浆 LDL-C 的变异中，与较低胆结石病风险相关的变异被映射到鞘糖脂生物合成途径，而与较高风险相关的变异被映射到与血浆脂蛋白组装、重塑和清除以及 ATP 结合盒转运蛋白相关的途径。这项 MR 研究提供了遗传证据，表明不同的血浆 LDL-胆固醇降低途径对胆结石疾病风险有相反的影响。