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Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

ABSTRACT: BACKGROUND:Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS:We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS:In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS:Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

SUBMITTER: Dewey FE

PROVIDER: S-EPMC5800308 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

Dewey Frederick E FE Gusarova Viktoria V Dunbar Richard L RL O'Dushlaine Colm C Schurmann Claudia C Gottesman Omri O McCarthy Shane S Van Hout Cristopher V CV Bruse Shannon S Dansky Hayes M HM Leader Joseph B JB Murray Michael F MF Ritchie Marylyn D MD Kirchner H Lester HL Habegger Lukas L Lopez Alex A Penn John J Zhao An A Shao Weiping W Stahl Neil N Murphy Andrew J AJ Hamon Sara S Bouzelmat Aurelie A Zhang Rick R Shumel Brad B Pordy Robert R Gipe Daniel D Herman Gary A GA Sheu Wayne H H WHH Lee I-Te IT Liang Kae-Woei KW Guo Xiuqing X Rotter Jerome I JI Chen Yii-Der I YI Kraus William E WE Shah Svati H SH Damrauer Scott S Small Aeron A Rader Daniel J DJ Wulff Anders Berg AB Nordestgaard Børge G BG Tybjærg-Hansen Anne A van den Hoek Anita M AM Princen Hans M G HMG Ledbetter David H DH Carey David J DJ Overton John D JD Reid Jeffrey G JG Sasiela William J WJ Banerjee Poulabi P Shuldiner Alan R AR Borecki Ingrid B IB Teslovich Tanya M TM Yancopoulos George D GD Mellis Scott J SJ Gromada Jesper J Baras Aris A

The New England journal of medicine 20170524 3

<h4>Background</h4>Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease.<h4>Methods</h4>We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human geneti ...[more]

PMID: 28538136

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Project description:BackgroundFamilial 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.ObjectivesThe 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.MethodsWe 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.ResultsThe 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).ConclusionsANGPTL3 deficiency is associated with protection from CAD.

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Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

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Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

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