Functional Polymorphism in the 5HTR2C Gene Linked to Enhanced Stress-Induced Cortisol Response

A study published in the journal Biological Psychiatry indicates that functional polymorphism in the 5HTR2C gene may contribute to altered stress reactivity, and to a specific endophenotype that may be linked to an increased risk of cardiovascular disease and type-2 diabetes.

Enhanced hypothalamic–pituitary–adrenal (HPA) axis and cortisol responses to stress have been linked to high levels of hostility, pathogenesis of the metabolic syndrome and cardiovascular disease incidence.

Serotonin acts at multiple sites to contribute to stress-induced HPA axis activation, and signaling through 5HTR2C receptors plays a key role in this process.

A single nucleotide polymorphism (SNP) – rs6318; 68G>C – that leads to a substitution of serine for cysteine at codon 23 (Cys23Ser) has been identified, and recent evidence indicates that the Ser23 C allele is constitutively more active than the Cys23 allele.

In the Biological Psychiatry study, Beverly Brummett and colleagues from the Department of Psychiatry, Duke University Medical Center, Durham, NC demonstrate that the cortisol  response  to  a  stress  task  was  significantly  larger in men hemizygous  for  the  Ser23  C  allele  compared  to  those  carrying the Cys23  G allele.

Men hemizygous for the Ser23 C allele of the 5HT2C rs6318 SNP had both larger cortisol responses and larger increases in anger and depressive mood during the stress protocol. This suggests that the 5HT2C receptor is at least partially responsible for the increase in both HPA axis function and negative moods under stress.

Previous research indicates that the Ser23 C variant is also associated with affective disorders, such as major depressive and bipolar disorder. This all together suggests that the rs6318 effects on 5HT2C receptor-mediated effects on both emotions and the HPA axis may be accounting, at least in part, for the linkages between depression and dysregulated HPA axis function.

Moreover, the authors discuss that elevated cortisol levels have been recently associated with a broad range of endophenotypes such as central obesity, elevated glucose, insulin and insulin resistance, higher blood pressure and lipids, as well as diseases – hypertension, coronary heart disease and type-2 diabetes.

Thus, according to the authors the  present  findings  may also indicate that men carrying  the  5HTR2C  Ser23  C  allele  may  be  more  likely than Cys23 G allele carriers to express these endophenotypes.

SOURCE:  Biol Psychol 2012, 89:94. Epub 2011 Oct 1.

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