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，而胆汁胆固醇则促进胆结石形成。不同的血浆低密度脂蛋白胆固醇降低途径可能对胆汁胆固醇产生不同的影响，从而影响胆结石疾病的风险。我们使用来自英国生物银行（30,547 例胆石病病例/336,742 例对照）、FinnGen（34,461 例/301,383 例对照）和日本生物银行（9,305 例/168,253 例对照）的数据进行了孟德尔随机化 (MR) 研究。我们首先进行了共定位证实的药物靶标 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-胆固醇与胆结石疾病风险之间关联的不同机制。对于血浆 LDL 胆固醇降低 1 个标准差，他汀类药物的基因模拟物与较低的胆结石疾病风险相关（比值比 0.72 [95% 置信区间 0.62，0.83]），但 PCSK9 抑制剂和靶向载脂蛋白 B 的基因模拟物与较低的胆结石疾病风险相关。与较高风险相关（1.11 [1.03, 1.19] 和 1.23 [1.13, 1.35]）。他汀类药物的关联得到了共定位的支持（后验概率 98.7%）。聚类 MR 分析确定了变异簇，显示血浆 LDL-胆固醇与胆结石疾病风险之间存在相反的关联，并有一些证据表明血统和性别特异性关联。 在降低血浆低密度脂蛋白胆固醇的变异中，那些与较低胆结石疾病风险相关的变异被映射到鞘糖脂生物合成途径，而那些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，表明不同的血浆低密度脂蛋白胆固醇降低途径对胆结石疾病风险具有相反的影响。