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ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.

Publication ,  Journal Article
Stitziel, NO; Khera, AV; Wang, X; Bierhals, AJ; Vourakis, AC; Sperry, AE; Natarajan, P; Klarin, D; Emdin, CA; Zekavat, SM; Nomura, A; Shah, SH ...
Published in: J Am Coll Cardiol
April 25, 2017

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.

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Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

April 25, 2017

Volume

69

Issue

16

Start / End Page

2054 / 2063

Location

United States

Related Subject Headings

  • Risk Factors
  • Myocardial Infarction
  • Mutation, Missense
  • Middle Aged
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Male
  • Lipids
  • Humans
  • Female
 

Citation

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Chicago
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Stitziel, N. O., Khera, A. V., Wang, X., Bierhals, A. J., Vourakis, A. C., Sperry, A. E., … PROMIS and Myocardial Infarction Genetics Consortium Investigators, . (2017). ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol, 69(16), 2054–2063. https://doi.org/10.1016/j.jacc.2017.02.030
Stitziel, Nathan O., Amit V. Khera, Xiao Wang, Andrew J. Bierhals, A Christina Vourakis, Alexandra E. Sperry, Pradeep Natarajan, et al. “ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.J Am Coll Cardiol 69, no. 16 (April 25, 2017): 2054–63. https://doi.org/10.1016/j.jacc.2017.02.030.
Stitziel NO, Khera AV, Wang X, Bierhals AJ, Vourakis AC, Sperry AE, et al. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol. 2017 Apr 25;69(16):2054–63.
Stitziel, Nathan O., et al. “ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.J Am Coll Cardiol, vol. 69, no. 16, Apr. 2017, pp. 2054–63. Pubmed, doi:10.1016/j.jacc.2017.02.030.
Stitziel NO, Khera AV, Wang X, Bierhals AJ, Vourakis AC, Sperry AE, Natarajan P, Klarin D, Emdin CA, Zekavat SM, Nomura A, Erdmann J, Schunkert H, Samani NJ, Kraus WE, Shah SH, Yu B, Boerwinkle E, Rader DJ, Gupta N, Frossard PM, Rasheed A, Danesh J, Lander ES, Gabriel S, Saleheen D, Musunuru K, Kathiresan S, PROMIS and Myocardial Infarction Genetics Consortium Investigators. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol. 2017 Apr 25;69(16):2054–2063.
Journal cover image

Published In

J Am Coll Cardiol

DOI

EISSN

1558-3597

Publication Date

April 25, 2017

Volume

69

Issue

16

Start / End Page

2054 / 2063

Location

United States

Related Subject Headings

  • Risk Factors
  • Myocardial Infarction
  • Mutation, Missense
  • Middle Aged
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Male
  • Lipids
  • Humans
  • Female