Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress.
BACKGROUND
Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease.


METHODS
We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST).


RESULTS
Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03).


CONCLUSIONS
We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders.
Kumsta
Robert
R
Department of Psychobiology, University of Trier, Trier, Germany.
Entringer
Sonja
S
Koper
Jan W
JW
van Rossum
Elisabeth F C
EF
Hellhammer
Dirk H
DH
Wüst
Stefan
S
D000222:Adaptation, Physiological / Q000235:genetics; D000223:Adaptation, Psychological; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000187:drug effects; D000328:Adult; D000704:Analysis of Variance; D003276:Contraceptives, Oral / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D015810:Linkage Disequilibrium; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012016:Reference Values; D012463:Saliva / Q000378:metabolism; D012737:Sex Factors; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
D003276:Contraceptives, Oral; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D004997:Ethinyl Estradiol; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone