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|Objective:||To investigate whether ANGPTL3 deficiency reduces the risk of coronary artery disease (CAD), based on genetic data from family and population studies, as well as biomarker levels in patients with a previous myocardial infarction (MI)|
|Study design:||Three lines of evidence to support this hypothesis were tested. First, CAD burden was assessed in individuals with complete ANGPTL3 deficiency; second, there was a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency; and third, biomarker levels in patients with MI were used to test whether lower circulating ANGPTL3 levels were associated with lower risk for CAD.|
In the population study, ANGPTL3 LOF variants were defined as either nonsense, frameshift, splice-site or missense variants that led to <25% of wild-type ANGPTL3 activity, as assessed by the percent change in circulating triglycerides and cholesterol levels in a mouse model.
The association of ANGPTL3 LOF mutations with levels of total cholesterol, LDL-C, HDL-C and log-transformed triglycerides was assessed by linear regression analysis, with adjustment for age, sex, study cohort, CAD status, principal components of ancestry, as well as the effect of lipid-lowering therapy. The association of ANGPTL3 mutations with risk of CAD was determined via meta-analysis with Cochran–Mantel–Haenszel statistics.
The association of circulating plasma ANGPTL3 concentration with MI was determined by multivariable logistic regression analysis, after stratification of the population by tertiles of ANGPTL3 concentration.
The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque.
Coronary calcium score was 0 Agatston units for these 3 individuals, compared with positive coronary calcium scores in 2 of 3 matched controls.
21 ANGPTL3 LOF variants were identified in the population analysis; these were common, carried by 1 in 309 people (heterozygous carriers).
Compared with individuals in the highest tertile, those in the lowest tertile of circulating ANGPTL3 concentrations had a 35% lower MI risk (adjusted odds ratio 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.0001). There was only modest attenuation after adjustment for LDL-C and triglycerides levels (odds ratio 0.71, p=0.0001).
|Authors’ conclusion:||Based on consistent findings from these three lines of evidence, the authors concluded that ANGPTL3 deficiency is associated with protection from CAD.|
ANGPTL3 decreases triglyceride-rich lipoproteins through by inhibition of lipoprotein lipase. As highlighted in previous reports on the R3i website, ANGPTL3 has been mooted as a potential therapeutic target for managing elevated triglycerides. The support for this proposal is based on mechanistic studies showing that ANGPTL3 plays a key role in the regulation of triglyceride-rich lipoprotein metabolism, family studies showing that complete deficiency of ANGPTL3 causes familial combined hypolipidemia, characterised by low levels of LDL-C, triglycerides and HDL-C, as well as studies in an animal model showing that knockout of ANGPTL3 expression is associated with reduced atherosclerotic burden.1-3 The key question arising from these reports is whether reduction in the functional capacity of ANGPTL3 in humans, using either genetic or pharmacotherapeutic approaches, could reduce coronary artery disease risk.
The results of this report provide proof of the concept that deficiency in ANGPTL3 not only has a favourable impact on plasma lipids, specifically lowering LDL-C and triglycerides, but also is associated with reduced plaque burden and protection against coronary artery disease. Thus, these findings provide a rationale for ongoing development of therapeutic approaches to ANGPTL3 inhibition, either via a monoclonal antibody or an antisense oligonucleotide. Indeed, in the last week, two new studies using either of these approaches have been published, showing substantial reduction in atherogenic lipoproteins, including plasma triglycerides, as well as reduction in atherosclerotic cardiovascular disease.4,5
Thus, there is clear support for the concept that targeting ANGPTL3 will reduce atherosclerotic cardiovascular disease. Will ANGPTL3 become the next PCSK9 in addressing the challenge of lipid-related residual cardiovascular risk? For the answer, we need to await further data investigating the potential of therapeutic approaches aimed at this novel target.
1. Shimizugawa T, Ono M, Shimamura M et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem 2002;277:33742–8.
2. Musunuru K, Pirruccello JP, Do R et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010;363:2220–7.
3. Ando Y, Shimizugawa T, Takeshita S et al. A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoEdeficient mice. J Lipid Res 2003;44:1216–23.
4. Dewey FE, Gusarova V, Dunbar RL et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017. doi: 10.1056/NEJMoa1612790. [Epub ahead of print]
5. Graham MJ, Lee RG, Brandt TA et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017. doi: 10.1056/NEJMoa1701329. [Epub ahead of print]