ANGPTL3 deficiency linked to reduced CAD risk
ANGPTL3 Deficiency and Protection Against Coronary Artery DiseaseLiterature - Stitziel NO, Khera AV, Wang X, et al. - JACC 2017; published online ahead of print
Angiopoietin-like protein 3 (ANGPTL3), which is secreted by the liver, is a potent inhibitor of lipoprotein lipase and endothelial lipase [1-3]. Loss-of-function (LOF) mutations causing a complete deficiency of ANGPTL3, as in the hereditary combined hypolipidaemia, leads to low triglycerides (TG), LDL-C, and HDL-C concentrations [4,5]. Hence, ANGPTL3 deficiency may reduce the risk for coronary artery disease (CAD), but this hypothesis has not been tested.
In this study, the coronary atherosclerotic plaque burden in 3 individuals with complete ANGPTL3 deficiency was compared with wild-type first-degree relatives. Moreover, the coding regions of ANGPTL3 were examined in 180,180 individuals and it was assessed whether LOF mutations are related to a lower risk of CAD. Furthermore, circulating ANGPTL3 biomarker levels were determined in patients with a first myocardial infarction and controls.
- The 3 participants with complete ANGPTL3 deficiency had a coronary calcium score of 0 Agatston units (AU), whereas 2 of the 3 matched control subjects had positive coronary calcium scores (6 AU and 610 AU, respectively).
- The total plaque burden was lower in the participants with complete ANGPTL3 deficiency (mean = 0%) compared with control subjects (mean = 39%).
- An ANGPTL3 LOF mutation was identified in 130 of 40,112 participants (0.32%, 95% CI 0.27-0.39). In individuals of European ancestry, most frequently observed inactivating variant was an intronic splice region variant rs372257803 (minor allele frequency = 0.17%). Accordingly, this variant was measured in an additional 8,066 CAD case subjects and 140,068 control subjects and identified 68 additional heterozygous carriers of an ANGPTL3 LOF mutation.
- Compared with non-carriers, individuals with a LOF ANGPTL3 mutation had 11% lower total cholesterol (P=0.0008), 12% lower LDL-C (P=0.04) and 17% lower TGs (P=0.01). HDL-C was not significantly different between groups (P=0.17).
- There was a 34% reduced risk of CAD among carriers of an ANGPTL3 LOF mutation compared with non-carriers (OR for carriers 0.66, 95% CI 0.44-0.98, P=0.04).
- Individuals in the lowest tertile of ANGPTL3 concentrations had significantly reduced risk of myocardial infarction compared with those in the highest tertile (adjusted OR 0.65, P=2.2*10-7).
Deep phenotyping in a family, gene sequencing in the population, and biomarker analysis in case and control subjects, showed that ANGPTL3 deficiency is associated with a reduced CAD risk. Analyses showed that coronary atherosclerotic plaque is absent in individuals with complete ANGPTL3 deficiency, that heterozygous carriers of an ANGPTL3 LOF mutations have a 34% reduction of CAD risk and that ANGPTL3 concentrations were lower in healthy controls compared to those presenting with myocardial infarction. These findings support the hypothesis that pharmacological inhibition of ANGPTL3 function may be useful in the treatment or prevention of CAD.
In his editorial article , Genest initially comments on the study of Stitziel et al with: ‘In a series of elegant studies, they provide compelling evidence that ANGPTL3 is causally related to CAD.’ He then discusses the findings in depth, and points out that the frequency of homozygosity or compound heterozygosity of the ANGPTL3 LOF mutation is rarer than homozygous familial hypercholesterolaemia. This makes the practical implications of the study results less important, since individuals with normal or low lipid levels, even if HDL-C is low as well, are not likely to undergo DNA testing for diagnostic reasons. Regarding ANGPTL3 as a therapeutic target, the author notes that a future inhibitor of the ANGPTL3 activity may not provide an additional benefit compared with existing lipid-lowering therapies, because the presence of only 1 LOF allele was related with only modest changes in the average lipoprotein phenotype. To mimic the effect of homozygous LOF on lipoprotein phenotype, a drug that completely inhibits ANGPTL3 activity will be required.
The author concludes: ‘Then, there’s the rub: We do not fully understand the physiological roles of ANGPTL3 and the mechanisms by which its inhibition lowers LDL cholesterol. The types of patients for whom such a drug would be considered are those with combined hyperlipidemia and the dyslipidemia of diabetes and metabolic syndrome. But these patients have an increased rate of production of apoB-containing particles (especially VLDL) from the liver. Increasing lipoprotein lipase activity by inhibiting ANGPTL3 could have the paradoxical effect of increasing the conversion of VLDL into LDL particles, an effect often seen with fibric acid derivatives. Therefore, it remains to be seen whether this finding will open therapeutic avenues for novel anti-ANGPTL3 therapies as an orphan drug and how might this extend to the more common dyslipidemias.’