Genetic Variant May Increase Risk of Stress-Induced Cardiovascular Damage

Duke University Medical Center
Thursday, 22 March 2001

Duke University Medical Center researchers have discovered that people who have a common variant of a specific gene are at a much greater risk of suffering adverse cardiovascular responses to mental stress.

This is important, the researchers say, because the damage caused to the heart and circulatory system by the body's chronic hyper-reactivity to stress ultimately can lead to coronary artery disease and death. Furthermore, they say, a simple genetic test can identify those at greatest risk so appropriate behavioral modification techniques can be used to minimize the damage in susceptible people.

"This is a very clear example of how someone's genetic makeup can interact with the environment to increase one's risks of cardiovascular disease," said lead researcher Dr. Redford Williams, who published the results of the Duke team's study today (March 23) in the journal Psychosomatic Medicine.

"This genetic variant appears to be a key factor in explaining the body's hyper-reactivity to stress, which, if it happens frequently enough and with enough strength, can lead to damage in the cardiovascular system," Williams continued. "No other study has been able to show such a strong link between genetics and environment causing an actual physiological response."

The research was supported by grants from the National Heart, Lung and Blood Institute, the National Institute of Mental Health and the National Institute on Aging, all parts of the National Institutes of Health, and the Fetzer Institute.

Cardiologists have known for some time that such factors as depression, anxiety and hostility are important risk factors for developing heart disease, and that these traits tend to cluster among people with such psychosocial traits as low socioeconomic status, smoking and alcohol abuse and excessive hormonal responses to stress.

The Duke researchers wanted to see if the brain chemical serotonin played any role in the body's hyper-reactivity to stress. They studied serotonin because it has been observed that low levels of this neurotransmitter are associated with certain negative personality and behavioral characteristics.

"Serotonin is a potent neurotransmitter that is involved in a wide range of bodily functions, as well as a major regulator of all emotions," Williams explained. "We know that many negative emotions, aggressive behavior and other negative behavioral traits such as eating disorders and substance abuse are also related to low levels of serotonin."

Specifically, the researchers wanted to see if there was any difference in the way people with different alleles of a known variant, or polymorphism, of the serotonin transporter gene responded to mental stress. This transporter regulates how much serotonin is taken back up after release and how it is used by the body. Drugs like Prozac, Zoloft and Paxil, for example, help reduce depression by blocking re-uptake of serotonin by the transporter.

Like all genes, each serotonin transporter gene has two alleles, one inherited from each parent. In the case of the serotonin transporter gene, alleles come in either a long or short form, meaning that every human has one of three possible combinations: two longs, a long and a short, or two shorts.

In their experiments, the Duke researchers took detailed physiological readings from 54 healthy volunteers at rest and during a standard battery of mental stress tests. These tests included samples from subjects' cerebrospinal fluid (CSF) and blood.

"When we compared how the body reacted during the experiments, we found that the people with the long allele of the polymorphism exhibited much greater blood pressure and heart rate responses when they were subjected to mental stress than those with the short allele," Williams said.

The subjects with one or two long alleles had 50 percent more of 5-HIAA, a byproduct that occurs as a result of the breakdown of serotonin, in their CSF.

"So here we have a specific polymorphism of a gene that is very important in the regulation of serotonin that also appears to regulate the body's cardiovascular response to mental stress, strongly suggesting that it could play an important role in the development of heart disease," Williams said.

The researchers found that people with the long-long and long-short variants both reacted equally negatively to the mental stress, which indicates the long allele is dominant, Williams said.

Interestingly, researchers know the global distribution of people with the long allele varies widely from region to region. For example, greater than 70 percent of Africans and African Americans possess at least one long allele of the serotonin transport gene, while 50 to 60 percent of people of European descent have the long allele and less than 30 percent of those from China and Japan have it.

While more studies are necessary to tease apart any interplay between the serotonin transporter gene and other genes, Williams said the results of the study raise the interesting possibility that the prevalence of the long allele in African Americans may explain their higher rates of hypertension, when compared to whites.

"Knowing a person's genetic status can help us immensely in taking preventative measures," Williams said. "People with the long allele could be offered stress-management training, which would likely reduce their risks of developing cardiovascular disease. Conversely, those with the short alleles may not need to be offered stress management."

Joining Williams in the study were Duke colleagues Douglas Marchuk, Dr. Kishore Gadde, John Barefoot, Dr. Katherine Grichnik, Michael Helms, Cynthia Kuhn, James Lewis, Dr. Saul Schanberg, Dr. Mark Stafford-Smith, Edward Suarez, Dr. Greg Clary, Ingrid Svenson and Ilene Siegler.

For more information, or to contact Duke University Medical Center, see their website at: www.mc.duke.edu