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Allele in Stress Reaction-linked Gene Associated with Cardiovascular Events, Death

NEW YORK (GenomeWeb Daily News) – A certain polymorphism in the stress-linked serotonin 2C receptor gene is linked to an increased risk of cardiovascular disease morbidity and mortality, researchers led by Duke University's Redford Williams reported in PLOS One yesterday.

The researchers examined the serotonin 2C receptor gene (5HTR2) in more than 6,100 patients undergoing cardiac catheterization at the Duke University Hospital, and found that the rs6318 Ser23 C allele was linked to a 38 percent increased risk of heart attack or death. This allele is present in about 13 percent of Caucasians.

"We've heard a lot about personalized medicine in cancer, but in cardiovascular disease we are not nearly as far along in finding the genetic variants that identify people at higher risk," said Williams, the director of the Behavioral Medicine Research Center at Duke in a statement.

Williams and his colleagues previously found that the rs6318 allele of the X-linked 5HTR2 gene is associated with a hypothalamic-pituitary-adrenal axis response to a stress recall test. In that study, published in Biological Psychology, the researchers reported that, when exposed to a stressful situation, men with that allele had twice as much cortisol in their blood as men without the variant. Variants in 5HTR2, the researchers noted, could modulate response to psychological stress.

"It is known that cortisol has effects on the body's metabolism, on inflammation, and various other biological functions that could play a role in increasing the risk of cardiovascular disease," said first author Beverly Brummett, an associate professor of psychiatry and behavioral sciences at Duke. "It has been shown that high cortisol levels are predictive of increased heart disease risk. So we wanted to examine this more closely."

In this study, the Duke team examined whether people with that variant had higher rates of cardiovascular-related morbidity and mortality. They recruited 6,126 Caucasians patients, including 4,036 men and 2,090 women, from the Duke cath lab, and followed them for a median 5.3 years. In that time, 1,769 events occurred, including 1,544 deaths and 225 myocardial infarctions.

The researchers genotyped the patients and collected data regarding cardiovascular disease risk factors such as BMI, smoking status, and diabetes history, among others.

The proportion of patients with clinical events was highest among male Ser23 C hemizygotes and female Ser23 C homozygotes, the researchers reported. Using a Cox regression model, they determined that, compared to Cys23 G carriers, the male Ser23 C hemizygotes and female Ser23 C homozygotes were at increased risk of all-cause death or MI.

After adjusting for other risk factors like age, BMI, smoking, and others, those groups remained at higher risk — a hazard ratio of 1.38 — of death or MI, though it was mitigated slightly.

"These findings suggest that this functional polymorphism of the 5HTR2C gene is associated with increased risk for CVD mortality and morbidity, but this association is apparently not explained by the association of rs6318 with traditional risk factors or conventional markers of atherosclerotic disease," Williams and his colleagues noted.

While the biological mechanism behind this effect remains unclear, the researchers suspect that the gene variants affect the level of cortisol, which influences levels of the collagen-degrading matrix metalloproteinase-9 protein. Then MMP-9 has an effect on the development of plaque, which, in turn, affects clinical events. The researchers noted in a statement that they are currently examining how MMP-9 softens plaques, leading to their release as clots that can cause MIs.

Still, the researchers argued that if their finding is replicated, it could influence how patients are treated. For instance, they noted that people with the 5HTR2C rs6318 Ser23 C could benefit from treatment with a 5HTR2C agonist like agomelatine. Additionally, behavioral interventions could be pursued to limit hypothalamic-pituitary-adrenal axis hyperactivity in carriers.

"The exciting part to me this is that this genetic trait occurs in a significant proportion of people with heart disease," Brummett added. "If we can replicate this and build on it, we may be able to find ways to reduce the cortisol reaction to stress — either through behavior modification or drug therapies — and reduce deaths from heart attack."

Williams is the founder of Williams LifeSkills, a firm that provides anger and stress management training.