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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
Secondary AuthorsKathiresan S
Corporate AuthorsPROMIS and Myocardial Infarction Genetics Consortium Investigators
JournalJ Am Coll Cardiol
Volume69
Issue16
Pagination2054-2063
Date Published2017 Apr 25
ISSN1558-3597
KeywordsAdult, Angiopoietin-like Proteins, Angiopoietins, Animals, Atherosclerosis, Case-Control Studies, Coronary Artery Disease, Female, Humans, Lipids, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mutation, Missense, Myocardial Infarction, Risk Factors
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
R33 HL120781 / HL / NHLBI NIH HHS / United States
RG/08/014/24067 / / British Heart Foundation / United Kingdom
R01 HL127564 / HL / NHLBI NIH HHS / United States
RC2 HL101834 / HL / NHLBI NIH HHS / United States
MR/L003120/1 / / Medical Research Council / United Kingdom
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