This article is more than 5 years old. Information may no longer be current.
ANGPTL3 loss-of-function mutation may confer lower risk for CAD
Click Here to Manage Email Alerts
Individuals with a deficiency of angiopoietin-like 3 had a decreased risk for CAD, even in the presence of risk factors, according to findings in the Journal of the American College of Cardiology.
Angiopoietin-like 3 (ANGPTL3) is associated with lower LDL, HDL and triglycerides and operates as an effective inhibitor of lipoprotein lipase and an endogenous inhibitor of endothelial lipase. The researchers analyzed whether ANGPTL3 deficiency was also associated with reduced risk for CAD.
Nathan O. Stitziel, MD, PhD, assistant professor of medicine, cardiovascular division, assistant professor of genetics at Washington University School of Medicine in St. Louis and Cardiology Today Next Gen Innovator, reviewed data from three participants who have inherited compound heterozygous loss-of-function mutations in the ANGPTL3 gene and matched them with three first-degree relatives who did not carry the mutation.
All three family members with ANGPTL3 deficiency had very low plasma lipid concentrations. One participant with the deficiency reported a history of hypertension, type 2 diabetes and previous tobacco use.
Researchers used coronary CTA to calculate participants’ coronary artery calcium score. Those with ANGPTL3 deficiency had a CAC score of 0 Agatston units while two of the three relatives without the deficiency had a CAC score > 0. In participants with ANGPTL3 deficiency, their total plaque burden was lower (mean, 0%) compared with the control group (mean, 39%).
Population effects
To review the effects of ANGPTL3 deficiency on the population, Stitziel and colleagues analyzed data from previous studies to see whether the mutations contributed to a lower risk for CAD compared with those without ANGPTL3 deficiency.
Data from ANGPTL3 gene sequencing from participants with CAD (n = 13,194) and without it (n = 26,198) were available for review. The researchers found that one in 309 participants had the ANGPTL3 loss-of-function mutation (0.32%; 95% CI, 0.27-0.39).
Researchers reviewed plasma lipid levels (n = 20,092). Those carrying the ANGPTL3 loss-of-function mutation had 17% lower triglyceride levels (P = .01), lower LDL (P = .04) and lower total cholesterol (P = .0008) when compared with participants who were not carriers of the mutation.
A cohort-based meta-analysis was executed to establish the link between the risk for CAD and loss-of-function mutations in ANGPTL3. Carriers of the mutation had a 34% reduction in the risk for CAD (OR = 0.66; 95% CI, 0.44-0.98) compared with noncarriers.
ANGPTL3 concentrations in participants who had their first MI and those who did not were also analyzed. Those with lowest concentrations had significantly reduced risk for MI vs. those with the highest concentrations (adjusted OR = 0.65; P = 2.2 x 10–7). After adjusted for observed plasma LDL and triglycerides, the result was moderately attenuated (adjusted OR = 0.71; P = .0001).
The researchers also conducted a biomarker study measuring circulating ANGPTL3 concentration in 1,493 individuals with MI and 3,232 controls without MI. They found that those in the lowest tertile of circulating ANGPTL3 concentration had reduced odds of MI compared with those in the highest tertile (adjusted OR = 0.65; 95% CI, 0.55-0.77).
Future treatment options
“This study adds ANGPTL3 to the list of therapeutic targets for coronary disease, which includes ANGPTL4, APOC3, LPA, NPC1L1 and PCSK9, that have been validated by finding [loss-of-function] mutations that associate with protection from disease, highlighting the promise and potential of human genetic studies in identifying such targets,” Stitziel and colleagues wrote.
“This association does not imply causality,” Jacques Genest, MD, professor at the department of medicine, division of cardiology at McGill University in Montreal, wrote in a related editorial. “Furthermore, the presence of one [loss-of-function] allele was associated with modest changes in the average lipoprotein phenotype. This is important because a small molecule that decreases ANGPTL3 activity might produce only a modest benefit compared with currently available lipid-lowering agents.” – by Darlene Dobkowski
Disclosure: Stitziel reports receiving a research grant from AstraZeneca and consultant fees from Aegerion Pharmaceuticals. Please see the full study for the other researchers’ relevant financial disclosures. Genest reports no relevant financial disclosures.
Perspective
Back to Top
Robert Roberts, MD, MACC, FRSC, FRCPC, LLD (Hon.)
Overall, what these findings add is we all recognize — and it’s been proven now for decades — that a major culprit in [CAD] and in the precipitation of [MI] is cholesterol. We’re always looking for ways to lower cholesterol, particularly LDL. Our major and almost only approach until recently has been that of inhibiting the synthesis of cholesterol, which gave rise to the class of statin therapy. Then recently, PSCK9 came along, which was identified as a genetic defect associated with increased heart disease, or its loss of function associated with decreased heart disease, and that served as a target for a new therapy that is now approved by the FDA.
This particular finding gives us another route whereby we can lower cholesterol. Certainly, it will be a few years before that target can be exploited to see whether it is effective and safe, but it is in the same category. All of us recognize that there are complications, even though they’re probably in the 2% or 3% range, and some people would say more for complications from statin therapy.
The findings clearly add to our knowledge that we have a new target on which we could develop new therapy. When that target comes to us through a genetic defect, we already have considerable data from families who have been around 30, 40 or 50 years with that particular gain or loss of function, so it not only gives us an idea that it should be an effective means to lower cholesterol, but it suggests that it’s also safe.
These data go further than that. They show through Mendelian randomization that this is a causative target for LDL and triglycerides, and so this is truly a rich body of knowledge that for pharmacology, gives a good target expected to turn out to be positive.
Keeping in mind, last year, the FDA only approved four drugs for treatment of CVD. It takes about 12 years and over $2 billion to develop a successful drug, mostly because 90% of the drugs in development fail. Here’s a drug that’s just starting development, but findings like these indicate it may succeed. If it’s safe, this is a good target. Even if development takes as long as PSCK9 inhibitors, which took less than 10 years, there is hope and positivity on the horizon.
There are few implications for clinical practice at this moment. If someone has a gain-of-function mutation, then that would have clinical implications. You would have to treat them more intensely because with gain of function, they will have higher cholesterol.
Further research will involve confirming these findings. The real research that we want to see done now is using this as a target and viewing the animal models to see what the mechanism is. This appears to have the same rationale, same logic, and promise as was seen with PSCK9 inhibitors.
Click Here to Manage Email Alerts