Related Experiment Video

Updated: Jul 29, 2025

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Genetically instrumented LDL-cholesterol lowering and multiple disease outcomes: A Mendelian randomization

Kitty Pham1, Anwar Mulugeta1,2,3, Amanda Lumsden1,2

  • 1Australian Centre for Precision Health, Clinical & Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

British Journal of Clinical Pharmacology
|May 19, 2023
PubMed

Insights

Genetically lowering LDL cholesterol is linked to 10 diseases, including cardiovascular conditions. This study also found effects on lung function and brain volume, suggesting broader impacts of cholesterol management.

Area of Science:

  • Genetics
  • Cardiovascular Medicine
  • Biomarkers

Background:

  • Lipid-lowering medications are crucial for managing cholesterol and cardiovascular health.
  • Understanding the causal links between LDL cholesterol reduction and various health outcomes is essential.

Purpose of the Study:

  • To investigate associations between genetically predicted LDL cholesterol lowering and a wide range of disease outcomes and biomarkers.
  • To explore potential causal relationships using Mendelian randomization.

Main Methods:

  • A Mendelian randomization phenome-wide association study (MR-PheWAS) was conducted in 337,475 UK Biobank participants.
  • Four genetic risk scores for LDL-C lowering (PCSK9, HMGCR, NPC1L1, LDLR) were analyzed against 1135 disease outcomes and 52 biomarkers.
  • Multiple sensitivity analyses and false discovery rate correction were applied.

Main Results:

  • Genetically instrumented LDL lowering showed associations with 10 distinct disease outcomes, supporting potential causality.
  • Genetic instruments for LDL lowering were directionally consistent with hyperlipidemia and cardiovascular diseases.
  • LDL-C lowering via PCSK9 was associated with lung function (FEV, FVC), and via HMGCR with hippocampal volume.

Conclusions:

  • Genetic evidence supports both beneficial and detrimental effects of LDL-C lowering across different pathways.
  • Further research is warranted to elucidate the impact of LDL-C lowering on lung function and brain volume changes.
Abstract

Keywords:
Mendelian randomizationUK Biobankcholesterollipid loweringlow-density lipoproteinphenome-widestatins

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