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Common Polymorphisms in the Glucocorticoid Receptor Gene Are Associated with Adrenocortical Responses to Psychosocial Stress

Department of Psychobiology (S.W., I.S.F., R.K., D.H.H.), University of Trier, Johanniterufer 15, 54290 Trier, Germany; and Department of Internal Medicine (E.F.C.V.R., J.W.K.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Stefan Wüst, Ph.D., Department of Psychobiology, University of Trier, Johanniterufer 15, 54290 Trier, Germany. E-mail: wuest{at}uni-trier.de.

Chronic dysregulation of hypothalamus-pituitary-adrenal axis activity is related to several stress-related disorders. Evidence suggests that polymorphisms in the glucocorticoid receptor (GR) gene may have an impact on this neuroendocrine system.

In the present investigation, 112 healthy males were studied to estimate the impact of three GR gene polymorphisms (BclI RFLP, N363S, ER22/23EK) on cortisol and ACTH responses to psychosocial stress (Trier Social Stress Test) and pharmacological stimulation (1 µg ACTH_1–24, 0.5 mg dexamethasone).

Because only four ER22/23EK heterozygotes were identified, these subjects were not statistically analyzed. Compared with subjects with the wild-type GR genotype (n = 36), 363S allele carriers (n = 10) showed significantly increased salivary cortisol responses to stress, whereas the BclI genotype GG (n = 18) was associated with a diminished cortisol response. BclI heterozygotes and homozygotes (GG) exhibited a trend toward lower ACTH responses, compared with wild-type subjects and 363S carriers. The cortisol response to ACTH_1–24 administration was not significantly different between genotypes. After dexamethasone ingestion, 363S carriers showed a trend toward an enhanced cortisol suppression.

This is the first report documenting an impact of GR gene polymorphisms on cortisol (and perhaps ACTH) responses to psychosocial stress. These variants may contribute to the individual vulnerability for hypothalamus-pituitary-adrenal-related disorders.

This work was supported by the German Research Foundation, Grant FOR 255/2-1.

Abbreviations: BMI, Body mass index; DST, dexamethasone suppression test; GC, glucocorticoid; GR, glucocorticoid receptor; HPA, hypothalamus-pituitary-adrenal; n.s., not significant; RFLP, restriction fragment length polymorphism; TSST, Trier Social Stress Test; WHR, waist to hip ratio.

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