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Independent Causal Effect of Remnant Cholesterol on Atherosclerotic Cardiovascular Outcomes: A Mendelian

Eliano P Navarese1,2,3,4, Donna Vine5, Spencer Proctor5

  • 1Interventional Cardiology and Cardiovascular Medicine Research, Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland (E.P.N., K.G., J.K.).

Arteriosclerosis, Thrombosis, and Vascular Biology
|July 13, 2023
PubMed

Insights

Remnant cholesterol (RC) causally increases the risk of coronary artery disease (CAD), myocardial infarction (MI), and stroke. This risk is independent of low-density lipoprotein (LDL) cholesterol levels, suggesting new therapeutic targets.

Area of Science:

  • Cardiovascular Genetics
  • Lipid Metabolism
  • Epidemiology

Background:

  • Observational studies link remnant cholesterol (RC) to residual cardiovascular event risk post-low-density lipoprotein (LDL) lowering.
  • The causal role of RC in predicting coronary artery disease (CAD), myocardial infarction (MI), and stroke requires further investigation.

Approach:

  • A large-scale Mendelian randomization study utilized single-nucleotide polymorphisms for RC and LDL from genome-wide association databases.
  • Genetic variants served as instrumental variables to minimize confounding and reverse causation biases inherent in observational studies.
  • Data from 958,434 participants were analyzed to estimate genetic associations with cardiovascular outcomes.

Key Points:

  • Significant causal effects of RC were observed on the risk of CAD (OR, 1.51), MI (OR, 1.57), and stroke (OR, 1.23).
  • The association between RC and CAD/MI risk remained robust even after accounting for LDL cholesterol levels.
  • No evidence of pleiotropy was found, strengthening the causal inference.

Conclusions:

  • This study demonstrates a strong genetic causal link between RC and major cardiovascular outcomes.
  • The cardiovascular risk associated with RC is independent of LDL cholesterol, highlighting RC as a distinct risk factor.
  • Future therapeutic strategies should prioritize early screening and long-term inhibition of RC.
Abstract

Keywords:
cholesterolcoronary artery diseasemyocardial infarctionriskstroke

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