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. 2017 Apr 25;69(16):2054-2063.
doi: 10.1016/j.jacc.2017.02.030. Epub 2017 Apr 3.

ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

Nathan O Stitziel  1 , Amit V Khera  2 , Xiao Wang  3 , Andrew J Bierhals  4 , A Christina Vourakis  5 , Alexandra E Sperry  5 , Pradeep Natarajan  2 , Derek Klarin  6 , Connor A Emdin  2 , Seyedeh M Zekavat  7 , Akihiro Nomura  2 , Jeanette Erdmann  8 , Heribert Schunkert  9 , Nilesh J Samani  10 , William E Kraus  11 , Svati H Shah  11 , Bing Yu  12 , Eric Boerwinkle  12 , Daniel J Rader  13 , Namrata Gupta  7 , Philippe M Frossard  14 , Asif Rasheed  14 , John Danesh  15 , Eric S Lander  7 , Stacey Gabriel  7 , Danish Saleheen  16 , Kiran Musunuru  17 , Sekar Kathiresan  18 ; PROMIS and Myocardial Infarction Genetics Consortium Investigators
Affiliations

ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

Nathan O Stitziel et al. J Am Coll Cardiol. .

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 <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.

Keywords: human genetics; loss-of-function mutations; myocardial infarction.

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Figures

FIGURE 1
FIGURE 1. Coronary CT Angiography in Humans With and Without Complete ANGPTL3 Deficiency
Representative sagittal computed tomography (CT) angiogram images show the right coronary artery (arrow) in (A) an individual with complete angiopoietin-like 3 (ANGPTL3) deficiency and (B) a matched first-degree relative without an ANGPTL3 mutation demonstrating calcified (open triangle) and noncalcified (closed triangle) plaque. (C) Total plaque burden representing the percentage of the coronary system affected by atherosclerosis is plotted by ANGPTL3 deficiency status.
FIGURE 1
FIGURE 1. Coronary CT Angiography in Humans With and Without Complete ANGPTL3 Deficiency
Representative sagittal computed tomography (CT) angiogram images show the right coronary artery (arrow) in (A) an individual with complete angiopoietin-like 3 (ANGPTL3) deficiency and (B) a matched first-degree relative without an ANGPTL3 mutation demonstrating calcified (open triangle) and noncalcified (closed triangle) plaque. (C) Total plaque burden representing the percentage of the coronary system affected by atherosclerosis is plotted by ANGPTL3 deficiency status.
FIGURE 1
FIGURE 1. Coronary CT Angiography in Humans With and Without Complete ANGPTL3 Deficiency
Representative sagittal computed tomography (CT) angiogram images show the right coronary artery (arrow) in (A) an individual with complete angiopoietin-like 3 (ANGPTL3) deficiency and (B) a matched first-degree relative without an ANGPTL3 mutation demonstrating calcified (open triangle) and noncalcified (closed triangle) plaque. (C) Total plaque burden representing the percentage of the coronary system affected by atherosclerosis is plotted by ANGPTL3 deficiency status.
FIGURE 2
FIGURE 2. Mouse Model to Functionally Annotate ANGPTL3 Missense Variants
(A) This schematic illustrates the design of the mouse study and circulating triglyceride (TG) and total cholesterol (TC) levels of wild-type (WT) and Angptl3 knockout (KO) mice generated with CRISPR-Cas9, before and after treatment with adenovirus (AdV) expressing WT human ANGPTL3 (11 WT mice, 18 KO mice). (B) The effects of mutant ANGPTL3 alleles expressed from AdV in KO mice (5 to 6 in each group) on TG levels are shown as percentages of the effect of AdV expressing the WT ANGPTL3 allele on TG. Mutant ANGPTL3 alleles that had <25% of the WT allele effect on TG levels were annotated as loss-of-function alleles. (For additional details, including TC levels of mice before and after AdV injection, see Online Figure 3.) Abbreviations as in Figure 1.
FIGURE 3
FIGURE 3. Association of ANGPTL3 Loss-of-Function Mutations with Risk of CAD
The association of ANGPTL3 mutations with risk of coronary artery disease (CAD) was determined via meta-analysis utilizing Cochran–Mantel–Haenszel statistics for ethnicity-specific stratified 2-by-2 tables. A reduced risk of CAD was noted among carriers of an ANGPTL3 loss-of-function variant (odds ratio of disease for carriers: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). AA = African ancestry; ARIC = Atherosclerosis Risk in Communities; ATVB = Italian Atherosclerosis Thrombosis and Vascular Biology; EA =European ancestry; ESP-EOMI = Exome Sequencing Project Early-Onset Myocardial Infarction; JHS = Jackson Heart Study; MI = myocardial infarction; OHS = Ottawa Heart Study; PROCARDIS = Precocious Coronary Artery Disease; PROMIS = Pakistan Risk of Myocardial Infarction Study; REGICOR = Registre Gironi del COR (Gerona Heart Registry); WTCCC = Wellcome Trust Case Control Consortium; other abbreviations as in Figure 1.
CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. ANGPTL3 Deficiency and Protection From Coronary Artery Disease
Multiple lines of evidence suggesting that angiopoietin-like 3 (ANGPTL3) deficiency is associated with protection from coronary artery disease (CAD). (A) A genotype-guided callback study of human “knockouts” for ANGPTL3, which used detailed atherosclerotic phenotyping, demonstrated an absence of coronary atherosclerotic plaque in individuals with complete ANGPTL3 deficiency. (B) Genomic analysis of ANGPTL3 loss-of-function variants, including missense variants that were experimentally found to disrupt ANGPTL3 function, found in up to 180,180 individuals showed a 34% reduction in risk of CAD among loss-of-function variant carriers. (C) Circulating ANGPTL3 protein concentrations were lower in healthy controls as compared to those presenting with a myocardial infarction.
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