Brian R Walker1, Ruth Andrew, Brigitte Escoubet, Maria-Christina Zennaro. 1. British Heart Foundation Centre for Cardiovascular Science (B.R.W., R.A.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Assistance Publique-Hôpitaux de Paris (B.E.), Hôpital Bichat-Claude Bernard, 75018 Paris, France; Unité Mixte de Recherche 1138 (B.E.), INSERM, Centre de Recherche des Cordeliers, 75006 Paris, France; Université Paris Diderot (B.E.), Sorbonne Paris Cité, 75018 Paris, France; Unité Mixte de Recherche en Santé 970 (M.-C.Z.), INSERM, Paris Cardiovascular Research Center, 75015 Paris, France; University Paris Descartes (M.-C.Z.), Sorbonne Paris Cité, 75006 Paris, France; and Assistance Publique-Hôpitaux de Paris (M.-C.Z.), Hôpital Européen Georges Pompidou, Service de Génétique, 75015 Paris, France.
Abstract
CONTEXT: Mineralocorticoid receptors (MRs) contribute to the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis in rodents. Studies with MR antagonists suggest a similar role in humans. OBJECTIVE: The objective of the study was to establish whether loss-of-function mutations in NR3C2, encoding MR, cause activation of the HPA axis. DESIGN AND SETTING: This was a case-control study in members of pedigrees from the PHA1.NET cohort, comprising patients with pseudohypoaldosteronism type 1 (PHA1) who are heterozygous for loss-of-function mutations in NR3C2 and healthy controls who are unaffected family members. PARTICIPANTS: Twelve adult patients with PHA1 (six men, six women) and 20 age-matched healthy controls (seven men, 13 women) participated in the study. RESULTS: Patients with PHA1 had higher morning plasma cortisol (816 ± 85 vs 586 ± 50 nmol/L, P = .02) and increased 24-hour urinary excretion of cortisol metabolites (985 ± 150 vs 640 ± 46 μg/mmol creatinine, P = .03), independently of gender. After adjustment for gender, age, PHA1 diagnosis, and percentage body fat, higher plasma cortisol was associated with higher plasma renin, lower serum high-density lipoprotein-cholesterol, and higher waist circumference but not with blood pressure, carotid intima-media thickness, or echocardiographic parameters. CONCLUSIONS: Haploinsufficiency of MR in PHA1 causes HPA axis activation, providing genetic evidence that MR contributes to negative feedback in the human HPA axis. With limited sample size, initial indications suggest the resulting hypercortisolemia is related to the severity of MR deficiency and has adverse effects mediated by glucocorticoid receptors on liver lipid metabolism and adipose tissue distribution but does not adversely affect cardiac and vascular remodeling in the absence of normal signaling through the MR.
CONTEXT: Mineralocorticoid receptors (MRs) contribute to the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis in rodents. Studies with MR antagonists suggest a similar role in humans. OBJECTIVE: The objective of the study was to establish whether loss-of-function mutations in NR3C2, encoding MR, cause activation of the HPA axis. DESIGN AND SETTING: This was a case-control study in members of pedigrees from the PHA1.NET cohort, comprising patients with pseudohypoaldosteronism type 1 (PHA1) who are heterozygous for loss-of-function mutations in NR3C2 and healthy controls who are unaffected family members. PARTICIPANTS: Twelve adult patients with PHA1 (six men, six women) and 20 age-matched healthy controls (seven men, 13 women) participated in the study. RESULTS: Patients with PHA1 had higher morning plasma cortisol (816 ± 85 vs 586 ± 50 nmol/L, P = .02) and increased 24-hour urinary excretion of cortisol metabolites (985 ± 150 vs 640 ± 46 μg/mmol creatinine, P = .03), independently of gender. After adjustment for gender, age, PHA1 diagnosis, and percentage body fat, higher plasma cortisol was associated with higher plasma renin, lower serum high-density lipoprotein-cholesterol, and higher waist circumference but not with blood pressure, carotid intima-media thickness, or echocardiographic parameters. CONCLUSIONS: Haploinsufficiency of MR in PHA1 causes HPA axis activation, providing genetic evidence that MR contributes to negative feedback in the human HPA axis. With limited sample size, initial indications suggest the resulting hypercortisolemia is related to the severity of MR deficiency and has adverse effects mediated by glucocorticoid receptors on liver lipid metabolism and adipose tissue distribution but does not adversely affect cardiac and vascular remodeling in the absence of normal signaling through the MR.