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Updated: Jun 21, 2025
Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles
Published on: November 10, 2017
Multi-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density
Guoyi Yang1,2, Amy M Mason3,4, Dipender Gill5
1School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. yanggy@connect.hku.hk.
Insights
Different ways to lower low-density lipoprotein (LDL)-cholesterol have opposing effects on gallstone disease risk. Statins may reduce risk, while PCSK9 inhibitors and apolipoprotein B targeting might increase it.
Area of Science:
- Genetics and Cardiovascular Disease Epidemiology
- Metabolic Disease Research
Background:
- Elevated plasma low-density lipoprotein (LDL)-cholesterol is a known risk factor for coronary artery disease.
- Biliary cholesterol accumulation is a primary driver of gallstone formation.
- The impact of various LDL-cholesterol lowering strategies on gallstone disease risk remains unclear.
Purpose of the Study:
- To investigate the distinct effects of different plasma LDL-cholesterol lowering pathways on gallstone disease risk using Mendelian randomization.
- To identify specific genetic mechanisms linking plasma LDL-cholesterol to gallstone formation.
Main Methods:
- A large-scale Mendelian randomization (MR) study utilizing data from UK Biobank, FinnGen, and Biobank Japan.
- Drug-target MR analyses with colocalization to assess the impact of LDL-cholesterol lowering therapies.
- Clustered MR and pathway analyses to explore underlying mechanisms and identify distinct genetic associations.
Main Results:
- Genetic variants mimicking statin use were associated with a reduced risk of gallstone disease (OR 0.72).
- Genetic variants mimicking PCSK9 inhibitors and targeting apolipoprotein B were associated with increased gallstone disease risk (ORs 1.11 and 1.23, respectively).
- Pathway analyses revealed distinct genetic associations for gallstone risk reduction (glycosphingolipid biosynthesis) versus risk increase (lipoprotein metabolism, ABC transporters).
Conclusions:
- Different pathways for lowering plasma LDL-cholesterol exert opposing effects on gallstone disease risk.
- Statin-like pathways appear protective against gallstones, whereas PCSK9 inhibition and apolipoprotein B targeting may increase risk.
- These findings highlight the importance of considering specific lipid-lowering mechanisms in the context of gallstone disease prevention.
Abstract:
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.
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