Heart attack risk – polymorphism of 5htr2c serotonin gene
In the December 2013 issue of PLOS One, a research team from the Department of Psychiatry, Duke University Medical Center, Durham, NC reports that a functional polymorphism of the 5HTR2C gene is associated with a 38% increased risk for cardiovascular disease events. This includes mortality and myocardial infarction (MI), independent of several traditional risk factors, and over a 7-year follow-up period.
In 2012, the same research group found that a functional polymorphism in the 5HTR2C Gene is linked to enhanced stress-induced cortisol response. These previous findings suggest that individuals carrying the rs6318 Ser23 C allele will be at higher risk for CVD compared to Cys23 G allele carriers. The present study examined allelic variation in rs6318 as a predictor of coronary artery disease (CAD) severity and a composite endpoint of all-cause mortality or myocardial infarction (MI) among Caucasian participants.
Of note, it has been proposed that one way genes influence the development and course of coronary heart disease (CHD) is via moderation of the effects of environmental stressors on brain mechanisms that regulate expression of behavioral and biological endophenotypes that are proximately involved in cardiovascular disease (CVD) pathogenesis and the precipitation of clinical CVD events.
The X chromosome gene encoding the serotonin 2C receptor (5HTR2C) is an attractive candidate to be playing such a role. This receptor plays a key role in mediation of stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation by stress-induced release of serotonin in the central nervous system, leading to attempts to identify variants in the 5HTR2C gene that might moderate the HPA axis response to psychological stress. As per the authors, one such 5HTR2C variant that has received considerable attention is a coding nonsynonymous single nucleotide polymorphism (SNP) – rs6318; 68G>C – which leads to a substitution of serine for cysteine at codon 23 (Cys23Ser). The frequency of the Ser23 C allele is approximately 13% in unrelated Caucasians.
Cortisol, produced by the adrenal glands’ cortex is the end-product of the HPA axis activation, and a major stress hormone. And psychological stress, anger, hostility, depression and social isolation are well-known factors contributing to the pathogenesis and course of cardiovascular diseases, especially myocardial infarction (MI).
The neurotransmitter serotonin is involved in the regulation of the stress response, and it acts at multiple levels in the brain or periphery to facilitate the stress-induced hypothalamic–pituitary–adrenal (HPA) axis activation.
In particular, the serotonin 5HTR2C receptor is among the key modulators of HPA axis, a major branch of the stress system. Signaling through the 5HTR2C receptor drives HPA axis activation mainly through the increase of corticotropin releasing hormone (CRH) release in the hypothalamic paraventricular nucleus.
Beverly H. Brummett et al., the authors of the PLOS One study found that a functional coding polymorphism in 5HTR2C, previously associated with enhanced cortisol response to psychosocial stress and intermediate CVD phenotypes, is also associated with a 38% increase in “end” CVD events over a 7-year follow-up period, supporting their hypothesis that mapping of intermediate traits can identify novel CVD genes.
These findings are consistent with the known function of 5HT2C receptors in the hypothalamic paraventricular nucleus (PVN), suggesting that corticotropin-releasing hormone (CRH), when stimulated by serotonin, may be mediating an increase in both HPA axis function and angry and sad moods.
The authors of the PLOS One study discuss the possible interactions between 5HT2C receptors, HPA axis activity, and levels of cortisol, anger, hostility and depression, and moreover, how these factors may contribute to inflammation, particularly related to unstable atherosclerotic plaques in the coronary arteries.
According to the authors, if replicated in other studies, these findings may indicate that behavioral and pharmacologic interventions to reduce HPA axis hyper-reactivity in individuals that are carriers of this polymorphism may become useful approach to improve prognosis and/or provide primary prevention from MI.
Source: PLoS One, 2013, 18;8(12):e82781. doi: 10.1371/journal.pone.0082781.
Read More: PLoS One
Updates
2014
A 2014 study validated the authors initial observation of association between rs6318 and cortisol response to an acute stressor, and extended the results to include females. Thus, persons homozygous for the Ser23 C allele had a significantly greater average cortisol response and area under the curve over the course of an emotional stress recall protocol.
Thus, as discussed by the authors, they provided further support for the proposition that the 5HTR2C receptor plays a role in the activation of the HPA axis by acute stress. Also they discussed that the identification of genes that might control cortisol reactivity to laboratory stressors may help explain individual variation in cortisol response during daily life.
Another 2014 study supported prior work that suggests a functional SNP on the HTR2C gene may confer an increased risk for depressive symptoms in White women with a history of significant life stress.
Precisely, the authors of this study showed that the cortisol response to a stress task was two-fold larger among those with the Ser23 C allele compared to those carrying the Cys23 G allele–providing evidence for the proposition that the 5-HT2C receptor plays a key role in the activation of the HPA axis by acute stress.
Demonstrating a stress by genotype interaction for females but not for males is consistent with at least some prior work. Of note, the authors discussed that both animal and human models show that females exhibit higher levels of glucocorticoids (cortisol or corticosterone) as compared to males.
2016
A 2016 study found that the Cys23 allele of the Cys23Ser 5-HT2C polymorphism was associated with greater cortisol reactivity in a social evaluative stressor task (TSST).
Furthermore, replication of the 5-HTTLPR’s association with cortisol reactivity provided additional evidence that this marker may influence the HPA axis. Taken together, as discussed by the authors, these findings underscore the importance of the serotonin system in regulating cortisol reactivity to stress.
Cover Image: Left panel: Serotonin 2C receptor gene structure. A) The human full-length 5-HT 2C gene, located on the X chromosome and processed from mRNA encoded from exon 3 to exon 6 after splicing out intronic sequence is depicted (not including 39-or 59-untranslated regions and not according to scale). B) The 5-HT 2C gene is translated into a seven-transmembrane G-protein coupled receptor. The editing cassette is located in the second intracellular loop. C) The nucleotide sequence of the 5-HT 2C editing cassette is depicted including the five nucleotide positions prone to adenosine to inosine editing. doi:10.1371/journal.pone.0032266.g001. From: Dynamic 5-HT2C Receptor Editing in a Mouse Model of Obesity. PLoS ONE 7(3):e32266 DOI:10.1371/journal.pone.0032266.
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