Mineralocorticoid receptor gene variants: implications for stress, blood pressure and personality (original) (raw)
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Psychoneuroendocrinology, 2011
Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency B0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.
European Journal of Pharmacology, 2008
The stress-response, including autonomic and hypothalamic-pituitary-adrenal (HPA) axis reactivity, is essential for maintaining homeostasis during a challenge. Brain mineralocorticoid receptors and glucocorticoid receptors operate in balance to coordinate the stress-response. Genetic variants in both the human mineralocorticoid and glucocorticoid receptor-genes have been functionally characterized. In vitro effects of these genetic variants on transactivation and mRNA stability have been described. In vivo, two mineralocorticoid receptor-gene SNPs (-2 G/C (allele frequency: 50%), MR I180V (11%)) and four glucocorticoid receptor-gene SNPs (ER22/23EK (3%), N363S (4%), BclI (37%), A3669G (15%)) are associated with changes in hypothalamic-pituitary-adrenal (HPA) axis reactivity. Importantly, the two mineralocorticoid receptor-gene variants (but none of the glucocorticoid receptor-gene variants) also associate with changes in autonomic output as measured as increased heart beat following a psychosocial stress (TSST). Moreover, several of these mineralocorticorticoid receptor-and glucocorticoid receptor variants have been found associated with stress-related disorders, including depression. These data indicate that dysregulation of mineralocorticoid-and glucocorticoid receptor are causative in the pathogenesis of depression. Moreover, these mineralocorticoid-and glucocorticoid receptor-gene variants constitute part of the genetic make up that determines individual stress-responsiveness inducing vulnerability to disease. Furthermore, mineralocorticoid-and glucocorticoid receptors are drug targets, thereby aiming at the underlying mechanisms of stress-related disorders.
Psychoneuroendocrinology, 2011
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 ...
Translational Psychiatry, 2011
Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency B0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.
Corticosteroid receptor polymorphisms: Determinants of vulnerability and resilience
European Journal of Pharmacology, 2008
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 MRgene SNPs (−2 G/C (50%), MR-I180V (11%)) showed in vitro changes in transactivational capacity, or affect stability of the mRNA (GR exon 9β 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, 9β 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.
Mineralocorticoid receptor-related markers and outcome of major depression
International Clinical Psychopharmacology, 2018
A close association between vegetative regulation and affect is common knowledge. Recently, the role of aldosterone and the activity of its receptor [mineralocorticoid receptor (MR)] in the clinical outcome for treatment with standard antidepressants has been shown including low systolic blood pressure and a low concentration of plasma sodium (Na +), both of which appear to be related to therapy resistance to standard antidepressants. We carried out a retrospective analysis of a double-blind placebo-controlled trial of St John's wort extract LI160 in 247 outpatients with major depression. The study did not show a difference between the treatment groups; therefore, a pooled dataset of the 6-week completer population of the trial was analyzed. The focus was on the moderating effect of blood pressure and electrolytes on clinical outcome (relative change in Montgomery-Asberg Depression Rating Scale). Low Na + /K + ratio and high K + at screening predicted worse outcome after 6 weeks as measures with the Montgomery-Asberg Depression Rating Scale (P < 0.01). Systolic blood pressure at the same time point did not influence the treatment outcome. In conclusion, signs of reduced peripheral MR sensitivity, as reflected by a lower plasma Na + /K + ratio and/or higher K + concentration, predict worse outcome. This is in line with our recent data as well as neuroendocrine findings. The data indicate that widely collected biomarkers, which are related to MR activity, may be useful to identify patients, who are at risk of nonresponse to antidepressant treatment.
Frontiers in Psychiatry, 2020
Adolescence is a critical developmental period characterized by heightened levels of depressive and anxiety symptoms. Experiencing chronic or environmental stress, for example, as a result of traumatic events or insensitive parenting, increases the risk for depression and anxiety. However, not all adolescents develop depressive or anxiety symptoms following environmental stressors, due to differences in stress resilience. One of the factors involved in stress resilience is enhanced functionality of the mineralocorticoid receptor (MR), one of the two brain receptors for the stress hormone cortisol. High levels of MR functionality result in relatively lower rates of depression, particularly in women that experienced stress. However, much less is known about MR functionality in relation to the development of adolescent depression and to other internalizing behavior problems such as anxiety. We therefore examined whether the effects of a functional MR haplotype (i.e., the MR CA haplotype) on the development of depressive and anxiety symptoms are sexdependent, as well as interact with environmental stressors. In a community sample of adolescents (N = 343, 9 waves between age 13 and 24), environmental stressors were operationalized as parental psychological control and childhood trauma. Results showed a sex-dependent effect of MR CA haplotype on the development of depressive symptoms but not for anxiety symptoms. MR CA haplotypes were protective for girls but not for boys. This study sheds more light on the sex-dependent effects of MR functionality related to the development of depressive and anxiety symptoms during adolescence.
GLUCOCORTICOID AND MINERALOCORTICOID RECEPTORS: Biology and Clinical Relevance
Annual Review of Medicine, 1997
Previous research found that variants of the glucocorticoid receptor (GR) (9, ER22/23EK, BclI, TthIIIl, NR3C1-1 and N363S) and mineralocorticoid receptor (MR) gene polymorphism (−2 C/G and I180V) are associated with both glucocorticoid (GC) sensitivity and major depressive disorder (MDD). There are no data which investigated prospectively whether these variants are associated with recurrence of MDD. Methods: Data were derived from the Netherlands Study of Depression and Anxiety (NESDA) which used the Composite International Diagnostic Interview (CIDI) to determine MDD. Polymorphisms in the GR and MR gene were determined and haplotypes were characterized. We analyzed in retrospect whether recurrent MDD (n = 951) in comparison with first onset MDD (n = 919) was associated with polymorphisms in the GR and MR gene. Furthermore, we analyzed prospectively for 4 years the time to recurrence among 683 subjects with a remitted MDD diagnosis. Time to recurrence of MDD was assessed using the CIDI and a life chart interview. Additionally, we analyzed interactions of the investigated polymorphisms with childhood trauma and recent negative life events.