ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.

TitleANGPTL3 Deficiency and Protection Against Coronary Artery Disease.
Publication TypeJournal Article
Year of Publication2017
AuthorsStitziel, NO, Khera, AV, Wang, X, Bierhals, AJ, A Vourakis, C, 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
Corporate AuthorsPROMIS and Myocardial Infarction Genetics Consortium Investigators
JournalJ Am Coll Cardiol
Volume69
Issue16
Pagination2054-2063
Date Published2017 Apr 25
ISSN1558-3597
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 

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 

CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

DOI10.1016/j.jacc.2017.02.030
Alternate JournalJ. Am. Coll. Cardiol.
PubMed ID28385496
PubMed Central IDPMC5404817
Grant ListKL2 TR001100 / TR / NCATS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
UM1 HG008895 / HG / NHGRI NIH HHS / United States
T32 HL007734 / HL / NHLBI NIH HHS / United States
R01 HL127564 / HL / NHLBI NIH HHS / United States
RC2 HL101834 / HL / NHLBI NIH HHS / United States
R21 HL120781 / HL / NHLBI NIH HHS / United States
K08 HL114642 / HL / NHLBI NIH HHS / United States
UM1 HG008853 / HG / NHGRI NIH HHS / United States
R01 HL131961 / HL / NHLBI NIH HHS / United States
RC1 TW008485 / TW / FIC NIH HHS / United States
R01 HL118744 / HL / NHLBI NIH HHS / United States