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Abstract
Objective Different serum lipids and lipid-modifying targets should affect the risk of cholelithiasis differently, however, whether such effects are causal is still controversial and we aimed to answer this question.
Design We prospectively estimated the associations of four serum lipids with cholelithiasis in UK Biobank using the Cox proportional hazard model, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Furthermore, we estimated the causal associations of the genetically predicted serum lipids with cholelithiasis in Europeans using the Mendelian randomisation (MR) design. Finally, both drug-target MR and colocalisation analyses were performed to estimate the lipid-modifying targets’ effects on cholelithiasis, including HMGCR, NPC1L1, PCSK9, APOB, LDLR, ACLY, ANGPTL3, MTTP, PPARA, PPARD and PPARG.
Results We found that serum levels of LDL-C and HDL-C were inversely associated with cholelithiasis risk and such associations were linear. However, the serum level of TC was non-linearly associated with cholelithiasis risk where lower TC was associated with higher risk of cholelithiasis, and the serum TG should be in an inverted ‘U-shaped’ relationship with it. The MR analyses supported that lower TC and higher TG levels were two independent causal risk factors. The drug-target MR analysis suggested that HMGCR inhibition should reduce the risk of cholelithiasis, which was corroborated by colocalisation analysis.
Conclusion Lower serum TC can causally increase the risk of cholelithiasis. The cholelithiasis risk would increase with the elevation of serum TG but would decrease when exceeding 2.57 mmol/L. The use of HMGCR inhibitors should prevent its risk.
- GALLSTONES
- GENETICS
- LIPIDS
- MOLECULAR EPIDEMIOLOGY
Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. The individual-level data from UK Biobank can be available for approved researchers via the link (https://www.ukbiobank.ac.uk/). The latest GLGC GWAS summary statistics can be accessed at http://csg.sph.umich.edu/willer/public/glgc-lipids2021/. The summary statistics of FinnGen GWAS data can be accessed at https://www.finngen.fi/en. The summary statistics of UKB GWAS can be accessed via https://pheweb.org/UKB-SAIGE/. Other genome-wide association studies can be accessed via the GWAS Catalog database (https://www.ebi.ac.uk/gwas/).
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Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. The individual-level data from UK Biobank can be available for approved researchers via the link (https://www.ukbiobank.ac.uk/). The latest GLGC GWAS summary statistics can be accessed at http://csg.sph.umich.edu/willer/public/glgc-lipids2021/. The summary statistics of FinnGen GWAS data can be accessed at https://www.finngen.fi/en. The summary statistics of UKB GWAS can be accessed via https://pheweb.org/UKB-SAIGE/. Other genome-wide association studies can be accessed via the GWAS Catalog database (https://www.ebi.ac.uk/gwas/).
Footnotes
LC and WQ contributed equally.
Contributors GL and LC proposed and designed the research. LC undertook data collection and performed the main data analysis. LC wrote the draft of the manuscript and ZF substantially revised the manuscript. WQ contributed to study design and data analysis in the revision. XS and WQ advised on the study design and revised the manuscript. MG supervised the statistical analysis and revised the manuscript. YZ and ML visualised the results and revised the manuscript. GL and ZF supervised the whole research and claimed the integrity of data analysis. GL accepted full responsibility for the work and the conduct of the study, had access to the data and controlled the decision to publish.
Funding The work is supported by the Natural Science Foundation of China (82241223, U20A20360), the Natural Science Foundation of Jilin Province (No. YDZJ202201ZYTS014) and the Financial Department of Jilin Province (Grant NO. JLSWSRCZX2020-045).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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