Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience

Why some individuals thrive and others break down under similar adverse conditions, is a central question in the neuroendocrinology of stress related psychopathology. The brain mineralocorticoid (MR) and glucocorticoid receptors (GR) operate in balance to coordinate behavioural, autonomic and neuroendocrine response patterns involved in homeostasis and health. Genetic variants of both the MR and GR have been functionally characterized. The four GR-gene single nucleotide polymorphisms (SNPs) (ER22/23EK (allele frequency: 3%), N363S (4%), BclI (37%), A3669G (15%)) and the two MR-gene SNPs (-2 G/C (50%), MR-I180V (11%)) showed in vitro changes in transactivational capacity, or affect stability of the mRNA (GR exon 9beta A3669G). All of these MR-and GR-SNPs change the regulation of the hypothalamus-pituitary-adrenal (HPA) axis at different levels including basal level (-2 G/C), dexamethasone induced negative feedback (ER22/23EK, N363S, BclI, 9beta A3669G) or following a psychosocial stress test (Trier Social Stress Test (TSST); all of the MR-and GR-SNPs). Importantly, the MR-I180V increased autonomic output and enhanced cortisol secretion during the TSST. Recently, several of these MR-and GR-variants have been found associated with psychopathology (depression, bipolar disorder). These data provide evidence that dysregulation of MR and GR are causative in the pathogenesis of depression and that these MR-and GR-gene variants are part of the genetic make up that determines individual stress-responsivity and coping style, affecting vulnerability to disease.