ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

J Am Coll Cardiol. 2017 Apr 25;69(16):2054-2063. doi: 10.1016/j.jacc.2017.02.030. Epub 2017 Apr 3.

Abstract

Background: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

Objectives: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

Methods: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

Results: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).

Conclusions: ANGPTL3 deficiency is associated with protection from CAD.

Keywords: human genetics; loss-of-function mutations; myocardial infarction.

MeSH terms

  • Adult
  • Angiopoietin-like Proteins
  • Angiopoietins / blood
  • Angiopoietins / deficiency*
  • Angiopoietins / genetics
  • Animals
  • Atherosclerosis / genetics
  • Case-Control Studies
  • Coronary Artery Disease / genetics*
  • Female
  • Humans
  • Lipids / blood
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Mutation, Missense
  • Myocardial Infarction / blood
  • Risk Factors

Substances

  • ANGPTL3 protein, human
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Lipids