ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

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 myocardial infarction (MI) patients – to test if 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 individuals with CAD and 158,200 controls. 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 individuals presenting with MI and 3,232 controls. RESULTS The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 individuals was a heterozygous carrier for an LOF mutation. Compared to 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.

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

“…In addition to the ANGPTL3 loss-of-function heterozygotes in this study, more than 200 heterozygous carriers and more than 20 homozygotes of ANGPTL3 loss-of-function variants have been reported by others with no apparent negative effects on cardiometabolic traits and diseases evaluated in these participants. 14,37,38 A recent study has shown an association between ANGPTL3 deficiency and protection from coronary artery disease, 38 a finding consistent with those of our study. In aggregate, these data support further investigation of inhibition of ANGPTL3 as a therapeutic target for lipid modification and possible reduction in the risk of atherosclerotic cardiovascular disease in humans.…”

Putative medicines that mimic mutations

“…See Letter p.573 disease, including heart attack. The researchers' finding is in agreement with a separate report 14 published this year. In addition, the authors of that earlier report used a computed tomographic technique to visualize blood vessels around the hearts of three people who had complete absence of ANGPTL3, and detected no atherosclerosis.…”

In Vivo Base Editing of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) as a Therapeutic Alternative to Genome Editing

“…13 As with genome editing, a single administration of a base-editing therapy would be expected to result in a prolonged and possibly lifelong reduction of cardiovascular risk. Furthermore, it should be feasible to efficiently base-edit multiple genes simultaneously with a single therapy, choosing among genes for which naturally occurring loss-of-function mutations in people are protective against cardiovascular disease and well-tolerated even in the complete absence of functional protein product, such as PCSK9 , 1,14 ANGPTL3 , 15,16 and APOC3 . 17–19 …”