Update on genetic testing for heart disease

It's complicated but promising. Here's what genes can tell us today.

What if a simple blood test could reveal with certainty your genetic predisposition for developing a serious, inherited form of heart disease? Would you take the test?

What if the test might reveal that you have a 50% increased risk of suffering a heart attack someday? Would you consider this knowledge worthwhile?

The advance knowledge you will develop heart disease and the decisions you face when you acquire this knowledge are two of the issues inherent in genetic testing as it stands today. Researchers are hard at work identifying specific genes and mutations (or variants) that play a role in the diagnosis, prognosis, and treatment of cardiovascular disease.

"Genetic testing is used for at least three purposes: to determine your risk for a common disease, such as heart attack; to know whether you have a gene variant that virtually assures you will develop a rare inherited disease; or to determine your response to, or side effects from, a particular drug," says Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital and a professor of medicine at Harvard Medical School.

But in order for so-called genotyping to be recommended, the information must be useful in helping with treatment decisions. "At this time, the value of genetic testing depends on your goals. For assessing risk of a common disease, like heart attack, I don't routinely offer genetic testing, because it's not clear that it helps with clinical decision-making at the present time," says Dr. Kathiresan.

Some answers are not helpful

Genetic tests look for the variants in a gene sequence that signal increased risk. You can have zero, one, or two copies of the variant. The more copies you have, the higher your risk. For example, there are about 30 sites in the DNA sequence that have been identified as increasing the risk of heart attack. If you carry more of the variants, your risk of heart attack may be twofold higher than those who carry fewer variants.

But what are you going to do with this information? Eat less? Exercise more? Stop smoking?

"We tell people to do these things anyway. It has not yet been shown that knowing they are at higher risk leads people to take better care of their health or helps doctors decide to treat you differently," says Dr. Kathiresan.

Medication response

Genetic testing can be useful in determining medication response. One genotyping success story involves clopidogrel (Plavix), a drug taken to prevent clots from forming inside a stent. Up to 30% of people have a gene variant that prevents their liver from activating the drug, putting them at increased risk for a clot-caused heart attack. A genetic test can tell whether a person has this gene variant.

"If you carry the variant, either the dose of clopidogrel must be raised, or you must be switched to a different antiplatelet agent, such as ticagrelor [Brilinta]," says Dr. Kathiresan.

A similar test touted to reveal a genetic variant that prevents an individual from benefiting from statin therapy was widely embraced, until the claim could not be validated. However, a test that shows an increased risk of debilitating, potentially dangerous muscle pain in response to statins may have value. "The question is, should everyone be tested?" says Dr. Kathiresan.

When genotyping is useful

For diagnosing inherited cardiac conditions controlled mainly by a single gene (called Mendelian diseases), genotyping may be more valuable. In some of these diseases, there is a very good correlation between having the gene variant and having the disease.

At the Center for Cardiovascular Genetics at Beth Israel Deaconess Medical Center, Dr. Saumya Das and his colleagues screen people, usually young people, with a family history of early sudden death or inherited diseases such as Marfan syndrome, hypertrophic cardiomyopathy, dilated cardiomyopathy at a young age, or arrhythmogenic right ventricular dysplasia. Often, these people have abnormal electrocardiograms, a history of unexplained fainting, or atrial fibrillation that cannot be explained by normal factors.

"Sometimes we see a clear Mendelian factor in diseases such as long Q-T syndrome and Brugada syndrome—two problems of electrical conduction that increase the risk of sudden death—that manifest at an earlier age. Knowing someone has the gene doesn't mean the management of the disease will change, but it does increase the likelihood we can screen relatives for the disease," says Dr. Das, who is also an assistant professor of medicine at Harvard Medical School.

"As of today, genetic tests don't add much to common clinical variables," he says. "We feel that may change. In the future, genomics might well allow us to stratify young people who are at high risk of sudden death and allow us to intervene to prevent it."