ANGPTL4 mutation ties lower triglycerides to lower CAD risk

View on the News

Path for future dyslipidemia therapies

The key finding in each study was that carriers of the E40K mutation and other rare mutations in ANGPTL4 had a lower risk of coronary artery disease than did noncarriers, a result that is consistent with the lower triglyceride levels and higher HDL cholesterol among mutation carriers.

These two studies that identify ANGPTL4 as a link between triglycerides and coronary heart disease not only improve our understanding of elevated triglycerides in heart disease, but also provide a path to the development of future therapies for dyslipidemia.

Dr. Sander Kersten, Ph.D., of the division of human nutrition at Wageningen University, the Netherlands, made these comments in an accompanying editorial (N Engl J Med. 2016 Mar 2. doi: 10.1056/NEJMe1601117). Dr. Kersten declared grant support from the Leducq Foundation, the European Foundation for the Study of Diabetes, the Netherlands Heart Foundation, and the Netherlands Organization for Scientific Research.




A genetic link between elevated triglycerides and coronary heart disease has been identified, opening up the possibility of a new treatment target.

Two separate studies have linked mutations in a gene associated with inhibition of the enzyme lipoprotein lipase – which reduces circulating triglycerides – to lower triglyceride levels and a lower risk of coronary artery disease. Both were published online on March 2 in the New England Journal of Medicine.

The first study reported the sequencing of the angiopoietin-like 4 (ANGPTL4) gene, which is responsible for a protein that inhibits the action of lipoprotein lipase.

One known mutation in this gene, the E40K variant, has previously been associated with decreased triglycerides and elevated HDL cholesterol, but its impact on coronary artery disease risk was unclear.

This sequencing, using samples from 42,930 predominantly European individuals, found the 17 (0.04%) participants who were homozygous for E40K had 13% lower triglycerides levels and 7% higher HDL cholesterol, compared with those without the mutation.

©Christian Jasiuk/Thinkstock

E40K mutation carriers also had a 4% lower risk of coronary artery disease per allele, compared with noncarriers, after adjustment for age, sex and ancestry.

In the same study, researchers looked at the effect of a monoclonal antibody against ANGPTL4 in five obese rhesus monkeys with dyslipidemia.

The treatment was associated with a 60% reduction in circulating triglyceride levels from baseline in four of the five monkeys and a 95% reduction in one monkey (N Engl J Med. 2016 Mar 2. doi: 10.1056/NEJMoa1510926).

“Our data support ANGPTL4 as a therapeutic target for inhibition through an antibody or other mechanism for reducing the risk of cardiovascular disease in humans,” wrote Dr. Frederick E. Dewey of the Regeneron Genetics Center, Tarrytown, N.Y., and coauthors.

Researchers also checked for evidence of the intestinal and mesenteric lymphadenopathy – which had been noted in some preclinical trials of the ANGPTL4 antibody – in individuals with the E40K mutation that inactivates ANGPTL4 – but found no increase in incidence, compared with noncarriers.

The second study reported on the DNA genotyping of 13,715 genes in 72,868 individuals with coronary artery disease and 120,770 controls without heart disease.

This revealed significantly increased risk associated with variants in the LPA and PCSK9 genes, both of which have previously been associated with coronary artery disease, but a significantly decreased risk of coronary artery disease associated with the same E40K variant of ANGPTL4 found in the first study.

When researchers looked at the effect of these variants on risk factors for coronary artery disease, they found the E40K variant was associated with significantly lower triglyceride levels and significantly higher HDL cholesterol levels per copy of the allele (N Engl J Med. 2016 Mar 2. doi: 10.1056/NEJMoa1507652).

Given the relationship between ANGPTL4, lipoprotein lipase, and heart disease risk, researchers postulated that mutations resulting in decreased function of lipoprotein lipase would increase triglyceride levels and the risk of coronary artery disease.

They identified a loss-of-function mutation in the lipoprotein lipase gene that was associated with an increased risk of coronary artery disease, and a gain-of-function mutation in the same gene that appeared to decrease the risk.

“Our results highlight LPL [lipoprotein lipase] as a significant contributor to the risk of coronary artery disease and support the hypothesis that a gain of LPL function or loss of ANGPTL4 inhibition protects against the disease,” wrote Dr. Nathan O. Stitziel of Washington University, St. Louis, and coauthors.

The first study was supported by Regeneron Pharmaceuticals. Several authors declared employment, stock holdings, institutional funding, and other support from Regeneron. One author declared a patent holding for an ANGPTL4 antibody, and five authors had no conflicts of interest to declare.

The second study’s authors declared a range of supporting grants and awards. Conflicts of interest declared included employment with and funding from pharmaceutical companies but many authors also reported no conflicts of interest.

Recommended Reading

Swapping saturated fat and refined carbs for healthy fats could ease global CHD burden
MDedge Cardiology
Warfarin is best for anticoagulation in prosthetic heart valve pregnancies
MDedge Cardiology
Heightened emphasis on sex-specific cardiovascular risk factors
MDedge Cardiology
MI, heart failure mortality rates slightly lower in VA hospitals
MDedge Cardiology
New ACC/AHA guidelines will curb DAPT duration for some
MDedge Cardiology
Greater myocardial inflammation found in RA patients after heart attack
MDedge Cardiology
STS: Risk score predicts rehospitalization after heart surgery
MDedge Cardiology
Noninvasive testing of women with suspected CAD simplified
MDedge Cardiology
Statins don’t appear to compromise effectiveness of abiraterone
MDedge Cardiology
Periop statins don’t prevent acute kidney injury after cardiac surgery
MDedge Cardiology