Human mineralocorticoid receptor (MR) gene haplotypes modulate MR expression and transactivation: Implication for the stress response Nienke van Leeuwen a,1 , Silja Bellingrath b,1 , E. Ronald de Kloet a , Frans G. Zitman c , Roel H. DeRijk a,c, * , Brigitte M. Kudielka b , Stefan Wu¨st d a Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden, The Netherlands b Jacobs Center on Lifelong Learning and Institutional Development, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany c Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands d Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany Received 3 June 2010; received in revised form 5 October 2010; accepted 6 October 2010 Psychoneuroendocrinology (2011) 36, 699—709 KEYWORDS Mineralocorticoid receptor (MR); Genetic polymorphisms; Stress Summary 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. * Corresponding author at: Div. of MedicalPharmacology, LACDR/LUMC,Gorlaeus Laboratories, P.O. Box 9502,2300 RA Leiden,The Netherlands. Tel.: +31 71 527 6229; fax: +31 71 527 4715. E-mail addresses: R.H.de.Rijk@LACDR.leidenuniv.nl, r.h.de.rijk@chem.leidenuniv.nl (R.H. DeRijk). 1 Both these authors contributed equally to this work. a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n 0306-4530/$ — see front matter # 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2010.10.003