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Stress gene tied to coronary risk

By Reid Creager

We’ve long heard and read how certain health risks and emotional stress can make us more susceptible to heart disease. Now a Duke University study provides evidence that a known “stress reaction gene” for some people with heart disease is linked to a greater risk of heart attacks and death.

According to Duke researchers, a genetic variant known to make some people extra sensitive to stress appears to be responsible for a 38 percent increased risk of heart attack in patients with heart disease. If this finding is validated through replication and future related studies, scientists can pursue behavior modification and drug therapies for patients in order to reduce deaths and disability from heart attacks.

The university’s finding is a byproduct of studies it has conducted on heart disease for more than a quarter-century in which it has emphasized the emotional system’s role in heart disease – the leading killer of both men and women in the United States.

“In my research program at Duke, since 1986 we have been supported by the National Heart Lung and Blood Institute to try to find psychosocial factors like hostility, anger and depression that play a role in the development of heart disease and its clinical course,” said Redford Williams Jr., M.D., senior author of the study and the director of the Behavioral Medicine Research Center at Duke University School of Medicine.

“We’re also trying to identify behaviors like smoking, not enough exercise, too much eating, all of which have been documented in hostile people, for example, and biological (factors) – overactive adrenaline and cortisol responses, etc. – that could be accounting for how you get from anger to blockage in your heart and a heart attack.”

He added that in the past dozen or so years, Duke has extended its research to try to identify variant genes “that are driving the expression of the biological and behavioral characteristics that are in the pathway to heart disease” – genes that may trigger these harmful factors.

Beverly Brummett, Ph.D. and associate professor of psychiatry and behavioral sciences at Duke, who was the study’s lead author, said the university has a unique approach to this field.

“A lot of other labs do work on genetic variants with respect to all disease outcomes,” she said. “But with regard to cardiovascular disease and the way we approach this ... I’m not aware of any labs that do it exactly the way we do. The foundation of our lab came from trying to study how the emotional system really influences cardiovascular disease.”

2 key components

Cortisol and serotonin are two important factors in the stress response. Cortisol – a steroid hormone produced by the adrenal gland, commonly known as a stress hormone – “has tons of effects on the body,” Williams said. “It raises your blood sugar; it makes your adrenaline receptors more sensitive to adrenaline; it inhibits your ability to fight infection.”

Williams said that in one of the studies cited in the Duke paper, published in December, “you can actually measure cortisol in hair. Your cortisol levels in your hair are an integrated reflection of the average level of cortisol that’s been in your blood for the last two to three months. This study found that the higher the hair cortisol, the more likely people were to have a heart attack.

“Given that, we were looking for genes that played a role in how much cortisol goes up under stress. There’s a serotonin receptor in your brain, that when it’s stimulated by serotonin – which is released in the brain when you’re under stress – causes cortisol to be secreted from your adrenal glands.”

The study published last month built on previous work at Duke and elsewhere that identified a variation in a DNA sequence known as a single nucleotide polymorphism (SNP), in which one letter in the genetic code is switched for another to change the gene’s function. Duke researchers focused on a SNP (also called a “snip”) occurring on the gene that makes a serotonin receptor and causes a hyperactive reaction to stress. Researchers reported that men with this genetic variant had twice as much cortisol in their blood when exposed to stress, compared with men without the variant.

Then, in light of cortisol’s harmful effects on the body, researchers used a large database of heart catheterization patients at Duke who were studied over several years. Genetic analyses were run on more than 6,100 white participants (two-thirds of them men). The 13 percent with the genetic variation for the overactive stress response had the highest rates of heart attacks and death over a median follow-up time of six years. The variation was associated with a 38 percent increased risk of heart attack and death.

“What’s exciting to me is that it was a hypothesis-driven, hypothesis-based study that got what we actually predicted we would get,” Brummett said.

A long process

Brummett and Williams emphasized that their most recent findings need independent replication and verification, and with studies involving a more diverse population. Williams explained that the 6,100 white participants in the recent study were simply “the highest frequency of patients in the Duke sample. The frequency and function of these mutations can be different in different races.”

However, heart disease’s impact is dramatic regardless of race. According to the latest statistics by the Centers for Disease Control and Prevention, it’s the leading cause of death for people of most ethnicities in the United States – including African-Americans, Hispanics and whites. Only cancer causes more deaths than heart disease in Native American Indians, Asians and Pacific Islanders.

Brummett said the need to stratify by race is just one reason that Duke’s latest study needs further exploration. She adds that the process is time-consuming, expensive and complex.

“First, it’s very difficult to find another sample to try to replicate this with,” she said. “We could go out and find another 9,000 people with cardiovascular disease, genotype them, but that’s really expensive. ... It’s not that we can’t replicate our study, but it’s very difficult.

“The other thing we’re trying to do is replicate what mechanisms might underlie that association. For example, antidepressants target the serotonin system, but it’s very difficult to find a way a particular snip will work in every person.”

She reminded that stress isn’t just about anger and worry: Depression and stress “are certainly linked.  … We know depression is so closely linked to coronary artery disease.”

Possible remedies

If the variant gene’s link to the increased probability of heart attacks is someday confirmed, science can then begin working to lessen the cortisol reaction to stress via behavior modification or drug therapies – which could reduce the number of heart attacks and deaths.

“As far as behavior modification, people with that particular genetic variant, you would want to target them more with regard to stress, things that can alleviate that,” Brummett said.

Added Williams: “It’s been shown that stress management training in women with breast cancer does reduce their cortisol levels, so that’s encouraging.”

Drug therapy would involve changing the function of that genetic variant, Brummett said, “similar to how SSRIs (selective serotonin reuptake inhibitors) change the function of the serotonin system in the brain.”

Williams said finding genetic variants linked to heart disease is a promising step toward more “personalized medicine,” as in cancer treatment. But that goal will first require years of further study, as well as money: Duke’s efforts hinge on getting another five-year grant from the National Heart, Lung and Blood Institute.

Meanwhile, other applications of the Duke team’s hypothesis are in the works, funds permitting.

“We’re going to study a group of people with genetic variations and genotype people who are going through stress reduction with regard to exercise protocol,” Brummett said.

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