Title | ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Stitziel 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 Authors | Kathiresan S |
Corporate Authors | PROMIS and Myocardial Infarction Genetics Consortium Investigators |
Journal | J Am Coll Cardiol |
Volume | 69 |
Issue | 16 |
Pagination | 2054-2063 |
Date Published | 2017 Apr 25 |
ISSN | 1558-3597 |
Keywords | Adult, 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. |
DOI | 10.1016/j.jacc.2017.02.030 |
Alternate Journal | J Am Coll Cardiol |
PubMed ID | 28385496 |
PubMed Central ID | PMC5404817 |
Grant List | KL2 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 |