Newly identified genetic errors may prevent heart attacks

March 2, 2016
Genetic errors identified in a new study led by Washington University School of Medicine in St. Louis may reduce risk of heart attacks and serve as a basis for developing new drugs designed to prevent heart disease. Credit: Sara Dickherber

To reduce risk of heart attack, the benefits of a healthy lifestyle are clear. But genetics can still stack the deck. Some people's genes bestow a natural advantage—or disadvantage—in protecting against heart disease, the leading cause of death worldwide.

Now, a new study that included genetic data from more than 190,000 people has identified two genes that, when altered in specific ways, either promote or undermine cardiovascular health. The findings may help guide efforts to design new preventive drugs, similar to the way statins now are prescribed to lower "bad" cholesterol to reduce the risk of heart disease.

The research, from Washington University School of Medicine in St. Louis, the Broad Institute at Massachusetts Institute of Technology and Harvard, and numerous other institutions, is published online March 2 in The New England Journal of Medicine.

"We identified genetic variation in several genes that associated with protection from ," said first author Nathan O. Stitziel, MD, PhD, a Washington University cardiologist and assistant professor of medicine and genetics. "Our findings support the idea that therapies focused on a major pathway regulating should help prevent the buildup of plaque in the heart's coronary arteries and protect against heart attacks."

To identify genes that might be relevant for drug discovery, the investigators plumbed DNA data from patients with coronary disease and from healthy controls. They searched across more than 220,000 genetic variants that altered proteins to identify those that appeared to influence . Errors in proteins can have major physiologic consequences.

As part of the study, the researchers confirmed past work identifying genes already shown to confer an advantage or a vulnerability in protecting against heart , and they implicated two new ones—ANGPTL4 and SVEP1. Rare errors in ANGPTL4 were associated with reduced risk of coronary artery disease. The reduction varied from 14 percent for a small error in the gene to cutting risk by about 50 percent when an entire copy of the gene was disabled. The other gene, SVEP1, showed the opposite correlation—a rare error increased risk of by about 14 percent.

While ANGPTL4 has been the subject of much study, the other gene newly implicated in cardiovascular health is a bit of a mystery. In the new study, Stitziel and his colleagues showed that the error in SVEP1 also was linked to higher blood pressure in their study populations, but beyond that there are few clues to what it's doing.

In contrast, ANGPTL4 has long been known to play a role in processing triglycerides, a type of fat that circulates in the bloodstream. Doctors measure levels of triglycerides as a marker of risk, though whether these fats play a role in causing plaque to build up in arteries historically has been a matter of debate. ANGPTL4's role in processing triglycerides is part of a system called the lipoprotein lipase (LPL) pathway. Blocking ANGPTL4 actually opens up this pathway, allowing the body to process triglycerides from the diet and get them out of the bloodstream.

"The gene's association with lower triglycerides has been known for a while," said Stitziel, who also sees patients at Barnes-Jewish Hospital. "But for a long time it was not clear that high triglycerides were a cause of coronary disease rather than a marker of it. Now we know that errors in ANGPTL4 associate with both reduced triglycerides and lower risk of coronary disease. This is another piece of the puzzle that points to a causal role for triglycerides in coronary disease."

"If that's correct, strategies to lower triglycerides should help," he added. "Our study indicates that those strategies could include blocking ANGPTL4 or manipulating other elements of the LPL pathway."

In people with a disabled copy of ANGPTL4, triglyceride levels in the blood are reduced by about 35 percent compared with people who have two working copies of the gene. Stitziel also pointed out that variations in the gene were not associated with changes in levels of "bad" LDL cholesterol. So any drug that impacts this pathway would, in theory, work independently of statins as well as PCSK9 inhibitors, a new and potent cholesterol-lowering therapy that was approved in 2015 by the Food and Drug Administration. Stitziel noted that these recently approved therapeutics that inhibit PCSK9 were developed after similar genetic studies showed an association with LDL cholesterol levels.

"The poster child for human genetic studies leading to new therapies is PCSK9," Stitziel said. "Rare errors in PCSK9 were first found to cause high LDL cholesterol and different errors were later associated with low LDL cholesterol and protection from coronary disease. And within 12 years of those findings there are now new therapies. The key insight from human genetic studies is the ability to identify biological pathways that are relevant to human disease."

With future therapeutics in mind, Stitziel pointed out that early versions of inhibitors targeting ANGPTL4 and other members of the LPL pathway are in development. While none of these are clinically approved therapies, the new study linking these genes to reduced coronary disease and lower triglycerides suggests the line of investigation is worth pursuing, he added.

As for the mystery gene implicated in the new study, Stitziel said he and researchers in his lab are now working to unravel the role of SVEP1 in risk.

Explore further: Errors in single gene may protect against heart disease

More information: Stitziel NO, et al. Investigators from the Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. The New England Journal of Medicine. March 2, 2016.

Related Stories

Errors in single gene may protect against heart disease

November 12, 2014
Rare mutations that shut down a single gene are linked to lower cholesterol levels and a 50 percent reduction in the risk of heart attack, according to new research from Washington University School of Medicine in St. Louis, ...

Study shows who benefits most from statins

March 3, 2015
New research suggests that widely used statin therapy provides the most benefit to patients with the highest genetic risk of heart attack. Using a relatively straightforward genetic analysis, the researchers assessed heart ...

US regulators give limited approval to cholesterol drug

July 25, 2015
US regulators on Friday approved a new cholesterol drug called Praluent, made by Sanofi and Regeneron, for people with certain genetic risk factors for heart disease.

Mutation leads to combined hyperlipidemia; genetic targeting may reverse it

February 5, 2014
(Medical Xpress)—A Yale study has identified the underlying genetic basis of combined hyperlipidemia, as well as a treatment that may normalize the condition. The study appears in Cell Metabolism.

Broken gene found to protect against heart disease

June 18, 2014
By scouring the DNA of thousands of patients, researchers at the Broad Institute, Massachusetts General Hospital, and their colleagues have discovered four rare gene mutations that not only lower the levels of triglycerides, ...

New hope for improved heart disease detection and treatment in type 2 diabetics

February 1, 2016
With approximately two-thirds of deaths among people with type 2 diabetes related to cardiovascular disease, a new report holds hope for improving the treatment of heart disease for one of the country's and the world's most ...

Recommended for you

Could this protein protect people against coronary artery disease?

November 17, 2017
The buildup of plaque in the heart's arteries is an unfortunate part of aging. But by studying the genetic makeup of people who maintain clear arteries into old age, researchers led by UNC's Jonathan Schisler, PhD, have identified ...

New model estimates odds of events that trigger sudden cardiac death

November 16, 2017
A new computational model of heart tissue allows researchers to estimate the probability of rare heartbeat irregularities that can cause sudden cardiac death. The model, developed by Mark Walker and colleagues from Johns ...

Popular e-cigarette liquid flavorings may change, damage heart muscle cells

November 16, 2017
Chemicals used to make some popular e-cigarette liquid flavorings—including cinnamon, clove, citrus and floral—may cause changes or damage to heart muscle cells, new research indicates.

Possible use for botulinum toxin to treat atrial fibrillation

November 16, 2017
From temporarily softening wrinkles to easing migraines, botulinum toxin has become a versatile medical remedy because of its ability to block nerve signals that can become bothersome or risky.

Proteome of the human heart mapped for the first time

November 15, 2017
A healthy heart beats about two billion times during a lifetime, thanks to the interplay of more than 10,000 proteins. Researchers from the Max Planck Institute of Biochemistry (MPIB) and the German Heart Centre at the Technical ...

First transcatheter implant for diastolic heart failure successful

November 15, 2017
Results presented today at the American Heart Association Scientific Sessions and published in Circulation show that a new device designed to treat diastolic heart failure is safe and effective. The first patient in the randomized, ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.