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Genetic Variant May Increase Risk of Stress-Induced Cardiovascular Damage

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Duke Health News 919-660-1306

DURHAM, N.C. - 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.

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