International Study Finds Mutated Gene Safeguards against Heart Attacks

Heribert Schunkert, MD, Technical University of Munich.

A broad comparative study conducted by an international team of researchers has found that people with a specific gene mutation have a 50% lower risk of suffering a heart attack than those without the mutation.¹ The research team, headed by cardiologist Heribert Schunkert, MD, professor of cardiology and medical director of the German Heart Center at the Technical University of Munich (TUM), theorizes that if the gene were switched off with medications, it could reduce the risk of coronary disease significantly.

“This discovery makes it considerably easier to develop new medications that simulate the effect of this mutation,” explains Schunkert. “This gives follow-on research aiming at reducing heart attacks in the future a concrete goal.”

FIGHTING HEART ATTACKS WITH BIG DATA

For the large-scale study, the scientists analyzed 13,000 different genes from a pool of 200,000 participants—both heart attack patients and healthy control persons. They were on the lookout for correlations between gene mutations and coronary artery disease.

The researchers registered such a correlation for a number of genes, including the angiopoietin-like 4 (ANGPTL4) gene. In addition, the researchers found that subjects with a mutated form of the ANGPTL4 gene had significantly lower triglyceride levels in their blood.

Jeanette Erdmann, Dr. rer. nat., University of Luebeck.

“The blood fat triglyceride serves as an energy store for the body. However, as with low-density lipoprotein (LDL) cholesterol, elevated values lead to an increased risk of cardiovascular disease,” explains study collaborator Jeanette Erdmann, Dr. rer. nat., professor and director of the institute of integrative and experimental genomics at the University of Lübeck. “Low values, by contrast, lower the risk.”

IMPORTANCE OF TRIGLYCERIDES UNDERESTIMATED

According to Schunkert, the significance of triglycerides in human health has been underestimated. “For most patients, the focus still lies on cholesterol. A differentiation is always made between healthy high-density lipoprotein (HDL) and harmful LDL cholesterol variants. In the meantime, however, we know that HDL values always run inversely proportional to those of the triglycerides, and that HDL itself actually tends to behave in a neutral manner.”

“Triglycerides, on the other hand, are the second-most-important blood fat, alongside harmful LDL cholesterol,” explains Schunkert. “The only reason HDL blood values are still measured is because HDL and triglyceride values together can be used to derive LDL values, which cannot be measured directly.”

Genetic variants influencing the lipoprotein lipase signal and the risk of heart attack. Illustration courtesy J Erdmann, University of Lübeck, New England Journal of Medicine. Click to expand.

The newly published study demonstrates that the concentration of triglycerides in the blood is influenced not only by nutrition and predisposition, but also by the ANGPTL4 gene. “At the core of our data is the lipoprotein lipase (LPL) enzyme, which causes the decomposition of triglycerides in the blood,” explains Erdmann.

Normally, ANGPTL4 restricts the action of the LPL enzyme, causing blood fat values to rise. The mutations identified by the researchers disable the function of ANGPTL4, and thereby ensure that triglyceride values drop significantly.

NEW APPROACH TO FIGHTING CORONARY DISEASE

“At the same time,” says Erdmann, “we discovered that the body does not even need the ANGPTL4 gene and manages wonderfully without it. It seems to be superfluous.” Shutting down the gene or inhibiting the LPL enzyme in another manner may ultimately protect against coronary disease.

“Based on our results, medications now need to be developed that neutralize the effect of the ANGPTL4 gene, thereby reducing the risk of a heart attack,” says Schunkert. “Other researchers have already done this successfully in animal tests. They drastically reduced the blood fat levels in monkeys that received a neutralizing antibody against ANGPTL4. This feeds the hope that antibody preparations with a similar effect can soon be used successfully in humans.”

The 4-year study involved 129 scientists from 15 countries. The work was funded in part by the European Research Council, the German Federal Ministry of Education and Research, the German Research Foundation, and the US National Institutes of Health.

REFERENCE

1. Stitziel N, Stirrups K, Masca N, et al. Coding variation in ANGPTL4, LPL, and SVEP1, and the risk of coronary disease. N Engl J Med. 2016; published online March 2, 2016; doi: 10.1056/NEJMoa1507652. Accessed March 7, 2016.