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Using multivariable Mendelian randomization to disentangle the causal effects of lipid fractions

Stephen Burgess1, Daniel F Freitag1, Hassan Khan1

  • 1Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom.

Plos One
|October 11, 2014
PubMed

Insights

High-density lipoprotein cholesterol (HDL-c) may be causally protective against coronary artery disease (CAD), independent of low-density lipoprotein cholesterol (LDL-c) and triglycerides. This finding suggests potential therapeutic benefits of targeting HDL-c for CAD risk reduction.

Area of Science:

  • Genetics
  • Cardiovascular Disease Epidemiology
  • Biochemistry

Background:

  • Previous studies suggested a causal role for LDL-c and triglycerides in CAD risk.
  • However, the causal link between HDL-c and CAD risk remained uncertain, with some evidence suggesting no significant association.

Purpose of the Study:

  • To investigate the independent causal effects of HDL-c, LDL-c, and triglycerides on coronary artery disease (CAD) risk.
  • To clarify the role of HDL-c in CAD etiology using advanced Mendelian randomization methods.

Main Methods:

  • Employed multivariable Mendelian randomization using published data.
  • Analyzed associations between 185 lipid-related genetic variants, lipid fractions (in 188,578 participants), and CAD risk (in 22,233 cases and 64,762 controls).
  • Focused on genetic variants without pleiotropic associations with blood pressure or BMI.

Main Results:

  • Multivariable Mendelian randomization indicated that HDL-c may be causally protective against CAD, independent of LDL-c and triglycerides.
  • Estimated odds ratios per standard deviation increase: LDL-c (1.57), HDL-c (0.91, p=0.028), triglycerides (1.29).
  • Results suggest HDL-c has an independent protective association with CAD risk.

Conclusions:

  • Interventions targeting HDL-c concentrations may influence CAD risk, though potentially to a lesser extent than LDL-c interventions.
  • The causal interpretation assumes no pleiotropic associations of genetic variants with other CAD risk factors.
  • Genetic predictors of LDL-c, HDL-c, and triglycerides demonstrate independent associations with CAD risk.
Abstract

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