Original ArticleSex Specific Associations between Common Glucocorticoid Receptor Gene Variants and Hypothalamus-Pituitary-Adrenal Axis Responses to Psychosocial Stress
Section snippets
Subjects
Initially, 601 healthy subjects were recruited from a Trier-based community sample and from students of the University of Trier. These subjects were genotyped for the GR variants under investigation. Subsequently, 206 subjects were selected for phenotyping according to their GR genotype, which resulted in a stratified sample of about equally sized comparison groups (see Results). This sample consisted of 118 females and 88 males (mean age 25.1 with SEM of ± 3.9 years, body mass index [BMI] 24.2
Genotyping
Genotyping of 601 subjects for the four polymorphisms revealed five haplotypes (see Figure 1). Observed haplotype frequencies corresponded to those previously reported (11, 18) and all SNPs were in Hardy Weinberg Equilibrium. The haplotype with the highest frequency (45%) will be referred to as the ‘Most Common Haplotype’ (MCH, Haplotype 1). The GAGAGG to GAAAAG transition at position 22/23 (2.5%) always occurred together with the G allele in exon 9β (Haplotype 2). In 13.5% of the subjects, A/G
Discussion
Variations of the GR gene can modulate the endocrine stress response and possibly represent one factor contributing to vulnerability for psychopathology (13, 18). Therefore, the present study investigated all GR gene polymorphisms, which, at present time, seem to be of functional relevance for the regulation of the HPA axis. The comparison of extreme response groups revealed significant associations between GR gene variants and HPA axis responses to psychosocial stress and one measure of GC
References (47)
- et al.
Glucocorticoid signalling--multiple variations of a common theme
Mol Cell Endocrinol
(1998) Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy
J Affect Disord
(2001)- et al.
Polymorphisms of the glucocorticoid receptor gene and major depression
Biol Psychiatry
(2006) - et al.
Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement
J Steroid Biochem Mol Biol
(1992) - et al.
Sex differences in HPA axis responses to stress: a review
Biol Psychol
(2005) - et al.
The effects of sex and hormonal status on the physiological response to acute psychosocial stress
Psychoneuroendocrinology
(2006) - et al.
Gender differences in hypothalamic-pituitary-adrenal (HPA) axis reactivity
Psychoneuroendocrinology
(2006) - et al.
Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population
J Lipid Res
(2004) - et al.
Evidence for sex-specific risk alleles in autism spectrum disorder
Am J Hum Genet
(2004) - et al.
Sex-specific genetic architecture of whole blood serotonin levels
Am J Hum Genet
(2005)
AUUUA motifs in the 3’UTR of human glucocorticoid receptor alpha and beta mRNA destabilize mRNA and decrease receptor protein expression
Steroids
The dominant negative activity of the human glucocorticoid receptor beta isoformSpecificity and mechanisms of action
J Biol Chem
Molecular mechanisms of glucocorticoid action and resistance
J Steroid Biochem Mol Biol
Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids
Endocr Rev
Stress and the brain: from adaptation to disease
Nat Rev Neurosci
The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis
Endocrine Rev
The metabolic syndrome--a neuroendocrine disorder?
Br J Nutr
The neuroendocrinology of chronic fatigue syndrome and fibromyalgia
Psychol Med
Sensitization of the hypothalamic-pituitary-adrenal axis in posttraumatic stress disorder
Ann N Y Acad Sci
Characterization of the BclI polymorphism in the glucocorticoid receptor gene
Clin Chem
Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index
Clin Endocrinol (Oxf)
Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition
Recent Prog Horm Res
Common Polymorphisms in the Glucocorticoid Receptor Gene Are Associated with Adrenocortical Responses to Psychosocial Stress
J Clin Endocrinol Metab
Cited by (160)
Moving beyond the mean: Promising research pathways to support a precision medicine approach to hormonal contraception
2023, Frontiers in NeuroendocrinologyCitation Excerpt :For example, HC users exhibit decreased anterior insula activation upon erotic stimulation and enhanced activation during monetary reward expectation (Abler et al., 2013; Bonenberger et al., 2013). Additionally, beyond these differences, research finds that HC use is associated with diminished libido (Boozalis et al., 2016; Casey et al., 2017; Smith et al., 2014), decreased perseverance on cognitive tasks (Bradshaw et al., 2020), and blunting of the HPA axis-mediated stress response (Kirschbaum et al., 1999; Kumsta et al., 2007; Lovallo et al., 2019; Merz, 2017; Nielsen et al., 2013; Rohleder et al., 2003; Roche et al., 2013). Despite the growing body of work demonstrating important psychobehavioral and neurophysiological differences between HC users and non-users, it is also clear that many of these effects are idiosyncratic and can vary considerably between both women and HC products.
Considerations into pharmacogenomics of COVID-19 pharmacotherapy: Hope, hype and reality
2022, Pulmonary Pharmacology and TherapeuticsThe clinical significance of the glucocorticoid receptors: Genetics and epigenetics
2021, Journal of Steroid Biochemistry and Molecular BiologyGeneralized and tissue specific glucocorticoid resistance
2021, Molecular and Cellular EndocrinologyCitation Excerpt :The ex vivo studies demonstrated maintained GC-induced up-regulation of GLIZ mRNA via transactivation, but decreased transrepression of IL-2 (van den Akker et al., 2006). Men carrying the GR-9β polymorphism exhibited enhanced ACTH response following the Trier Social Stress Test as well as higher ACTH levels and cortisol awakening response following a DST, suggesting a relative GC resistance (Kumsta et al., 2007). The 3669G allele was associated with reduced central obesity in women and a more favorable lipid profile in men from European origin, but not from South-Asian origin, suggesting an ethnicity-specific attenuation of the undesirable effects of GC on fat metabolism (Syed et al., 2006).
Stress & executive functioning: A review considering moderating factors
2020, Neurobiology of Learning and Memory