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Serotonin receptor polymorphism links stress reactions to cardivascular disease risk
Researchers in Duke University have uncovered a genetic polymorphism in a serotonin receptor gene that helps explain the link between risk and outcomes of cardiovascular disease (CVD) and reaction to mental stress. There is substantial evidence to suggest that there is a link between emotional stress responses, elevation of the stress hormone cortisol and morbidity and mortality for CVD. Illnesses such as depression are linked to incidence of heart disease.

The current study, published this week in PLoS ONE established that a polymorphism in the 5HTR2C gene for a serotonin receptor is significantly associated with the study end-point of all-cause mortality or myocardial infarction (MI) among Caucasian participants. Serotonin (5-HT) is a neurotransmitter which is intimately involved in regulation of mood, sleep and appetite. There are multiple serotonin receptors. The 5HTR2C, which is the subject of this study, mediates serotonin-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and hence release of cortisol. Illnesses such as depression, especially when associated with anxiety, tend to feature hyperactivity of the HPA axis.

The study focused on the rs6318 Ser23 C allele of the 5HTR2C gene. This allele had been previously associated in men with larger increases in plasma cortisol and higher subjective rating of negative emotions when remembering occasions that had made them happy or sad compared to carriers of the Cys23G allele. The allele was also linked to stronger adrenocorticotropic hormone (ACTH) responses, a measure of HPA activity, to an agonist of 5HTR2C. This allele has also been associated with, for example, higher central obesity, poorer glucose metabolism and higher levels of serum lipids, all of which can contribute to increased risk levels of CVD. The study population was 6126 Caucasian participants consecutively recruited through the cardiac catheterization laboratory at Duke University Hospital (Durham, NC) as part of the CATHGEN biorepository. The study showed that the rs6318 Ser23 C allele is associated with increased risk for CVD mortality and morbidity. The allele was not however, associated with traditional cardiac risk factors such as body mass index, diabetes, hypertension, dyslipidemia, smoking history, number of diseased coronary arteries, or left ventricular ejection.

The researchers are working on a hypothesis that the link between 5HTR2C via cortisol to increased CVD mortality and morbidity may lie with a recently demonstrated connection between cortisol to unstable atherosclerotic plaque in the coronary arteries. Cortisol has been associated with increased matrix metalloproteinase (MMP-9) which degrades collagen contributes to development of vulnerable plaques. Redford B. Williams Jr., M.D., the lead author of the study, is satisfied that their findings lead the way to helping to “ begin to develop and test early interventions for those heart patients who are at high risk of dying or having a heart attack."


Brummett BH, Babyak MA, Jiang R, Shah SH, Becker RC, et al. (2013) A Functional Polymorphism in the5HTR2C Gene Associated with Stress Responses Also Predicts Incident Cardiovascular Events. PLoS ONE 8(12): e82781. doi:10.1371/journal.pone.0082781

Duke Medicine. "Stress reaction gene linked to death, heart attacks." ScienceDaily, 19 Dec. 2013. [Accessed 20 Dec. 2013]
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