Harvard Heart Letter

Gene tests for some, not all

Genetic testing helps some people glimpse their cardiovascular future.

The announcement in April 2003 that scientists had worked out the order of the three billion letters in the human genetic code revved up the hopes and imaginations of many people, cardiologists included. Personal genetic report cards, mused a few, will someday help each of us better understand our heart disease risk and point the way to new treatments. They're right, of course. But "someday" will be a while coming "" the human genome isn't giving up its secrets easily, and some of what we're learning we don't quite know what to do with.

Heart disease has long been known to run in families. Some cardiovascular conditions are passed from parents to children in the same simple way that pea plants pass on traits such as seed color or pod shape. These conditions, caused by changes in a single gene, include hypertrophic cardiomyopathy, familial hypercholesterolemia, long QT syndrome, and Marfan syndrome, to name just a few.

Not all cardiovascular disease stems from such simple changes. Some genes increase the odds of developing heart disease but don't guarantee it. And a fair amount of it is the result of several genes, each of which is turned on or off, up or down, by diet, exercise, medications, the environment, and other genes.

So far, researchers have identified hundreds of genes that directly cause or subtly influence heart disease or stroke. Their tasks in the body range from regulating the amount of harmful LDL cholesterol in the bloodstream to controlling electrical communication between heart cells, influencing inflammation, determining the breakdown of fatty acids, and even setting the lifespan of certain cells.

What genes do

A gene is a strip of DNA that carries the code for a particular protein. Think of it as a stretch of letters that spells a useful word. A change of even one letter sometimes translates into a change in the protein. The most common changes, called polymorphisms, generally don't cause important changes in their corresponding proteins' shape or function. Mutations, which are less common, often cause disease by altering the function of a key protein.

The hunt is on

New molecular tools are making it easier than ever to identify genes linked to cardiovascular disease. That has several companies rushing to patent genes and develop genetic tests.

In October 2007, researchers with Celera, a gene-hunting company, presented a genetic risk score based on five genes linked with heart disease. Applying it to a long-term study of nearly 14,000 men and women from four geographically diverse communities, the company showed that those with the highest genetic risk scores were 57% more likely to have developed heart disease over a 13-year period than those with the lowest scores.

Already available tests such as the deCODE MI and deCODE AF also gauge heart disease risk. Both look for variants in particular genes. Being positive for these variants approximately doubles the chances of having an early heart attack or developing atrial fibrillation.

Academic scientists are also heavily involved in this line of work. For example, Harvard researcher Sekar Kathiresan and colleagues have identified a variety of genes and gene markers that are associated with everything from lipid levels to blood vessel stiffness and the heart's response to an exercise stress test.

Certainty vs. risk

The information you most want from a genetic test is whether or not disease X is in your future. You can get that kind of information from tests for genetic variations that directly cause heart disease. For example, carrying one or two of the genes for familial hypercholesterolemia invariably means you will have to battle very high cholesterol.

The results of the Celera or deCODE tests tell you about your risk for cardiovascular disease. A positive test doesn't mean you are destined to develop a cardiac problem, but that your risk is higher than average. At the same time, a negative test doesn't give you a clean bill of health. It means you are at average risk of developing these conditions.

Such tests may be helpful in a general sort of way, if they get people to pay more attention to their cardiovascular health. Few of the tests, though, point the way to particular therapies. If you had a high Celera genetic risk score, for example, your doctor would recommend the same steps "" eat a healthy diet low in saturated and trans fats, exercise, don't smoke, and reduce stress "" as if you had a low score.

Other benefits

An early payoff of the hunt for new heart disease genes will be better insight into how cardiovascular disease develops along with the discovery of new targets for treatment, says Dr. Christine Seidman, who directs the Cardiovascular Genetics Center at Harvard-affiliated Brigham and Women's Hospital.

She points to the identification of a gene called PCSK9. The 3% or so of people with one of several variants of this gene tend to have low levels of LDL. They are also far less likely to have heart attacks, need bypass surgery or angioplasty, or die of heart disease than those with the normal gene. Having a PCSK9 variant is twice as powerful as taking a cholesterol-lowering statin, probably because the gene is acting from birth onward, while most people don't start taking a statin until middle age. This suggests that earlier attention to LDL among people without a beneficial PCSK9 variant could translate into less heart disease.

Examining what this gene does will give researchers a clearer understanding of how the body controls LDL. And targeting this gene or its product could point the way to the next generation of cholesterol-lowering drug therapy.

Another early application of cardiovascular genetics will be to better tailor drug therapy for individuals. We'll focus on this field, called pharmacogenomics, in a future issue.

Who needs a genetic test?

Genetic testing may someday be a standard part of preventive medicine. Today, though, it makes sense mainly for individuals with a family member who has been diagnosed with a condition known to have a genetic cause. These include:

  • familial hypercholesterolemia

  • hypertrophic cardiomyopathy

  • dilated cardiomyopathy

  • long QT syndrome and other familial arrhythmias

  • Brugada syndrome

  • familial aortic aneurysm.

Having a genetic test is simple. You merely give a sample of blood, a swab of cells from the inside surface of the cheek, or a small piece of skin or other tissue.

These tests don't direct the treatment of cardiovascular disease "" that's the same whether the disease has a genetic or non-genetic cause. The real value of genetic testing is that it can alert family members who also have the problematic gene. By sounding an early warning, genetic testing can trigger early diagnosis and treatment, which can potentially save lives.

Despite the availability of some cardiovascular-related genetic tests on the Internet, this isn't yet a do-it-yourself proposition. Input from a trained counselor is invaluable for interpreting the results of a genetic test.