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Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis

Kiran Musunuru1, Sekar Kathiresan2

  • 1From the Department of Medicine, Harvard Medical School, Boston, MA (K.M., S.K.); Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (K.M.); Broad Institute of MIT and Harvard, Cambridge, MA (K.M., S.K.); and Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.).

Circulation Research
|February 20, 2016
PubMed

Insights

Human genetic studies indicate that specific lipoproteins, including lipoprotein(a) and triglyceride-rich lipoproteins, causally contribute to coronary heart disease (CHD) risk. Further research may explore new treatments targeting these lipids for CHD prevention.

Area of Science:

  • Cardiovascular Epidemiology
  • Human Genetics
  • Pharmacology

Background:

  • Observational studies link plasma lipids to coronary heart disease (CHD) risk but cannot establish causality.
  • Distinguishing correlation from causation in lipid biomarkers requires genetic and clinical trial data.

Purpose of the Study:

  • To evaluate the causal role of various plasma lipid biomarkers in the development of CHD.
  • To explore the potential for novel therapeutic targets beyond low-density lipoprotein (LDL) for CHD prevention.

Main Methods:

  • Analysis of human genetic data in conjunction with results from randomized controlled trials (RCTs) of lipid-modifying medications.
  • Examination of gene variants associated with plasma apolipoprotein B-containing lipoproteins and their correlation with CHD risk.

Main Results:

  • Genetic evidence supports low-density lipoprotein (LDL) as causal for CHD, while high-density lipoprotein (HDL) is not.
  • Surprisingly, genetic data suggest lipoprotein(a) and triglyceride-rich lipoproteins (TRLs) also causally contribute to CHD.
  • Gene variants increasing levels of apolipoprotein B-containing lipoproteins consistently elevate CHD risk.

Conclusions:

  • Genetic findings suggest that lowering TRLs and lipoprotein(a) may reduce CHD risk, complementing LDL reduction strategies.
  • Pharmacological targeting of TRLs and lipoprotein(a) represents a promising, yet unproven, avenue for CHD prevention.

Keywords:
atherosclerosiscoronary diseasegeneticslipoproteinstriglycerides

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