Polymorphisms of the glucocorticoid receptor gene and major depression.
BACKGROUND
The most consistent biological finding in patients with depression is a hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis, which might be caused by impaired glucocorticoid signaling. Glucocorticoids act through the glucocorticoid receptor (GR) for which several polymorphisms have been described. The N363S and BclI polymorphisms have been associated with hypersensitivity to glucocorticoids, whereas the ER22/23EK polymorphism is related to glucocorticoid resistance.


METHODS
We studied whether the susceptibility to develop a depression is related to these polymorphisms by comparing depressive inpatients (n = 490) and healthy control subjects (n = 496). Among depressed patients, we also investigated the relation between GR variants and dysregulation of the HPA-axis, as measured by the combined dexamethasone suppression/corticotropin-releasing hormone (CRH)-stimulation test, clinical response to antidepressive treatment, and cognitive functioning.


RESULTS
Homozygous carriers of the BclI polymorphism and ER22/23EK-carriers had an increased risk of developing a major depressive episode. We found no genetic associations with functional HPA-axis measures in depressed patients. The ER22/23EK-carriers, however, showed a significantly faster clinical response to antidepressant therapy as well as a trend toward better cognitive functioning during depression.


CONCLUSIONS
The BclI and ER22/23EK polymorphisms were associated with susceptibility to develop major depression. In addition, the ER22/23EK polymorphism is associated with a faster clinical response to antidepressant treatment. These findings support the notion that variants of the GR gene might play a role in the pathophysiology of a major depression and can contribute to the variability of antidepressant response.
van Rossum
Elisabeth F C
EF
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. e.vanrossum@erasmusmc.nl.
Binder
Elisabeth B
EB
Majer
Matthias
M
Koper
Jan W
JW
Ising
Marcus
M
Modell
Sieglinde
S
Salyakina
Daria
D
Lamberts
Steven W J
SW
Holsboer
Florian
F
D000328:Adult; D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000627:therapeutic use; D001216:Asparagine / Q000235:genetics; D016022:Case-Control Studies; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004252:DNA Mutational Analysis; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D003907:Dexamethasone / Q000008:administration & dosage; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012694:Serine / Q000235:genetics; D012720:Severity of Illness Index; D013997:Time Factors
D000928:Antidepressive Agents; D011965:Receptors, Glucocorticoid; D012694:Serine; D001216:Asparagine; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone