Impact of Gene-Gender Effects of Adrenergic Polymorphisms on Hypothalamic-Pituitary-Adrenal Axis Activity in Depressed Patients

Objective: There is overwhelming evidence that activation of the
hypothalamic-pituitary-adrenal (HPA) system plays a major role in
depression and cardiovascular disease in genetically susceptible
individuals. We hypothesized that due to the multiple interactions
between the sympathetic and the HPA systems via adrenoceptors,
polymorphisms in these genes could have an impact on HPA axis
activity in major depression. Methods: Using the
dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we
investigated the association of alpha 2-adrenoceptor (ADRA2A -1291C
-> G) and the beta 2-adrenoceptor gene (ADRB2 Arg16Gly) in 189
patients with major depression during the acute state of the
disease and after remission. Results: Male ADRA2A -1291G allele
homozygotes showed significant pretreatment HPA axis hyperactivity,
with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p =
0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In
contrast, female ADRB2 Arg/Arg homozygotes had increased
pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F =
8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective
genotypes, the stress hormones remained elevated in the second
DEX/CRH test, despite a reduction in depressive symptoms.
Conclusions: This study provides evidence that, depending on gender
and polymorphisms, there is continuous HPA axis overdrive in a
proportion of patients irrespective of the status of depression.
Considering the importance of stress hormones for cardiovascular
disorders, our data might suggest that these patients are at high
risk of comorbidity between depression and cardiovascular
disorders. Copyright (c) 2008 S. Karger AG, Basel