Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk
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Émilie Gobeil1, Jérôme Bourgault1, Patricia L Mitchell1
1Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, 2725 chemin Ste-Foy, Québec, QC G1V 4G5, Canada.
Background And Aims:
RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases.
Methods:
RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank.
Results:
In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60).
Conclusions:
PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.
Insights
Inhibition of angiopoietin-like protein-3 (ANGPTL3) strongly affects triglyceride levels but has minimal impact on atherosclerotic cardiovascular disease (ASCVD) risk. Near-complete ANGPTL3 inhibition may be necessary for reducing ASCVD in specific patient groups.
Area of Science:
- Genetics
- Cardiovascular Disease
- Metabolic Disorders
Background:
- Investigating angiopoietin-like protein-3 (ANGPTL3) inhibition for reducing lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk.
- Exploring RNA-based, antibody-based, and genome editing therapies targeting ANGPTL3.
- Utilizing Mendelian randomisation (MR) to assess causal links between ANGPTL3 variations and cardiometabolic outcomes.
Purpose of the Study:
- Determine if genetic variations in ANGPTL3 causally influence triglyceride and apolipoprotein B (apoB) levels.
- Assess the impact of ANGPTL3 variations on coronary artery disease (CAD), ischemic stroke (IS), and other cardiometabolic diseases.
- Evaluate the role of ANGPTL3 in lipid metabolism and ASCVD risk.
Main Methods:
- RNA sequencing and genome-wide genotyping to identify SNPs associated with ANGPTL3 liver expression.
- Analysis of genome-wide summary statistics for plasma ANGPTL3 protein levels (deCODE study).
- Investigation of ANGPTL3 protein-truncating variants (PTVs) in UK Biobank participants for effects on lipid levels, apoB, and CAD.
Main Results:
- Common genetic variants affecting ANGPTL3 expression strongly influenced triglyceride levels, modestly affected LDL cholesterol, and weakly affected apoB levels.
- No significant effect of common ANGPTL3 variants on CAD or other cardiometabolic diseases was observed.
- Carriers of rare ANGPTL3 PTVs showed lifelong reductions in triglyceride levels but only slightly lower apoB levels and similar CAD event rates compared to non-carriers.
Conclusions:
- ANGPTL3 genetic variations significantly impact triglyceride levels and weakly affect apoB levels, but do not appear to influence ASCVD risk.
- Rare ANGPTL3 PTVs lead to substantial triglyceride reduction with minimal impact on apoB and CAD risk.
- Substantial ANGPTL3 inhibition may be required to effectively reduce ASCVD risk in individuals with very high apoB levels.
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