Human mineralocorticoid receptor (MR) gene haplotypes modulate MR expression and transactivation: implication for the stress response.

Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in secretion of corticosteroids which facilitate behavioural adaptation. These effects exerted by corticosteroids are mediated by two brain corticosteroid receptor types, the mineralocorticoid receptor (MR), with a high affinity already occupied under basal conditions and the glucocorticoid receptor (GR), with a low affinity only activated during stress. Here, we studied MR gene haplotypes constituted by the two single nucleotide polymorphisms MR-2G/C (rs2070951) and MRI180V (rs5522). The haplotypes showed differences in cortisol-induced gene transcription and protein expression while the structural variant MRI180V did not affect ligand binding. Moreover, in a well characterized cohort of 166 school teachers these haplotypes have been associated with perceived chronic stress (Trier Inventory for the Assessment of Chronic Stress, TICS) and, in a subgroup of 47 subjects, with ACTH, cortisol and heart rate responses to acute psychosocial stress (Trier Social Stress Test, TSST). MR haplotypes were significantly associated with the TICS scales "excessive demands at work" and "social overload". Subjects homozygous for haplotype MR-2C/MRI180, which in vitro showed highest expression and transactivational activity, displayed the highest salivary cortisol (p<0.001), plasma cortisol (p=0.010), plasma ACTH (p=0.003) and heart rate (p=0.018) responses. It is concluded that the investigated MR haplotypes modulate cortisol-induced gene transcription in vitro. Moreover, these haplotypes may contribute to individual differences in perceived chronic stress as well as neuroendocrine and cardiovascular stress responses.