|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, Kathiresan, S|
|Corporate Authors||PROMIS and Myocardial Infarction Genetics Consortium Investigators|
|Journal||J Am Coll Cardiol|
|Date Published||2017 Apr 25|
|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|
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.
|Alternate Journal||J Am Coll Cardiol|
|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