American College of Physicians: Internal Medicine — Doctors for Adults ®


Heart-disease physician leads new research on genetics

Eric J. Topol, FACP, heads up cutting-edge search for connections that could alter cardiac screening, treatment

From the July-August ACP Observer, copyright 2006 by the American College of Physicians.

By Sarah Lovinger, ACP Member

The era of customized cardiac care based on a patient's genes may not be that far off.

That's the idea behind the genetic databank now being put together under the direction of Eric J. Topol, FACP, professor of genetics at Cleveland's Case Western Reserve University. Dr. Topol, one of the 10 most frequently cited medical researchers, is heading up a five-year, $18 million flagship grant sponsored by the National Institutes of Health to study the genetic information of 10,000 patients with suspected or known coronary atherosclerotic disease (CAD).

Eric J. Topol, FACP

So far, he and his team have studied patients' DNA, angiogram, plasma and serum with the goal of defining the genes for myocardial infarction (MI) and using that information as the basis for association studies, already underway. They are also expanding their repository of genetic information on African Americans with CAD.

In delving into the genomics of coronary disease, Dr. Topol admits he and his colleagues have a way to go before they catch up to cancer researchers, who likewise want to help tailor cancer treatments to individual genetic profiles. "They have had a big edge, because they have had tissue to work with," Dr. Topol said. "Cardiologists are at a disadvantage because all we have is the DNA."

Nonetheless, he predicts that genetic screening tests for cardiac conditions will be a reality within five years. He recently spoke with ACP Observer about what he and his research team have learned so far.

Q: What has been the biggest surprise of your research?

A: MI and coronary disease are not nearly as connected as we thought they would be. We thought that the same genes would be associated with developing the cholesterol plaque and also developing MIs.

What we’ve learned is that they’re very different processes from a genetic standpoint. There are some interlinking genes and connections, but they’re not nearly as tightly intertwined as we had expected.

Q: Is that good or bad news?

A: It's very good news, because cholesterol in the arteries doesn’t kill or destroy heart muscle. It can cause angina, but that can be treated with a stent or a bypass operation. On the other hand, it’s the cracking of the artery and the inflammation, the fissure, the plaque rupture, that is the killer of this disease—or at the very least what destroys heart muscle. So we’re fortunate that they are not so connected.

Q: What else have you discovered?

A: We found one gene—a deletion mutation in MEF2A associated with heart attacks and coronary disease--and have provided validation for two other heart attack genes: FLAP and LTA4.

Q: How long will it take for internists to feel the results of your research?

A: There’s a big lag between discovering genes and putting them into routine panels, probably four or five years. Things like PCSK9 [proprotein convertase subtilisin/kexin type 9, which modulates the LDL receptor number] will be part of that routine panel.

Q: What exactly will the impact be?

A: The field can go in many different directions. But I predict that five years from now, the average internist will be screening not only patients' individual risk of a heart attack, but also the [risks associated with their genetic] interactions with food, coffee, lifestyle and exercise.

It was recently reported, for instance, that a gene that is part of metabolizing coffee can be quite slow in some people, and drinking coffee may put these people at risk of heart attack. Perhaps people who like more than two cups of coffee a day and have a family history of heart attack should be screened.

Q: What can internists tell their patients now?

A: They can assure patients with a family history of heart attack that the [genetic] hunt is going on around the world and that within a matter of a few years most of the genes responsible for heart attacks will be fully known. Say an internist is seeing someone in their 30s or 40s who has a strong family history of heart attacks. It could well be that that individual doesn’t have any major genes for heart attack and won’t have to worry so much.

Q: What about the patient with a positive genetic result?

A: We can target [prevention efforts] to those people who really can benefit—and maybe they'll be more inclined to listen. It’s very hard to get people to change their lifestyle, and it takes a lot of persistence to keep working with people about their weight and diet and exercise. Knowing they have a genetic predisposition may markedly improve their lifestyle.

Q: How will this information affect drug therapy?

A: Today we give every person with coronary disease the same four or five different medicines.

For example, statins are the most frequently prescribed meds today—but about 90 out of 100 people [who take statins] only get the benefit of lowered LDL cholesterol. Their laboratory value improves, but so what? They don’t necessarily have any reduction in death, heart attack or stroke. What we need is to develop medicines and devices that can be coupled with patients' biologic underpinnings.

Q: Has your work shed light on race-specific concerns?

A: We are no longer talking about race and ethnicity; we are talking about ancestry, because you can define ancestry through the genome. About one-third of the genomic variance in each of the three main ancestries—European, Asian and African—is ancestry-specific, which means it is not shared by the other major ancestries.

It will turn out that heart attack is just like any other major condition: You have ancestry-specific genome issues. Already we know there's an almost 350% increased risk of heart attack in African Americans if they carry the leukotriene A4 gene. In European Americans, the increased risk is quite modest, more like 15%.

When we approach diseases of the future, we will have to have patients representing all three of those ancestries. That’s why we are building up the African American repository to complement the European one. We will also have to develop a big Asian one.

Q: What about information on risk for women?

A: It does not appear that gender is as big a deal as ancestry. We have not found any genes that are gender-specific yet, but we are going to continue looking.

Q: Where does your research go from here?

A: The next phase involves discovery of more heart attack genes through the technique of whole-genome association [the genotype analysis of subjects characterized in clinical studies]. We are pretty far along with this and believe it will be particularly fruitful.

We also use mouse heart attack models to confirm discoveries and delve into further mechanistic detail. It will take at least a few more years to determine the principal genes that either engender susceptibility to or provide protection from heart attacks.

Sarah Lovinger, ACP Member, is a freelance medical reporter based in Evanston, Ill., and a general internist who practices part-time in Chicago.

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.


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