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Glucocorticoid Receptor Gene (glucocorticoid + receptor_gene)
Selected AbstractsGENETIC STUDY: BclI glucocorticoid receptor polymorphism and smoking in the general populationADDICTION BIOLOGY, Issue 3 2009Satu J. Siiskonen ABSTRACT We studied the hypothesis that the BclI polymorphism of the glucocorticoid receptor gene is associated with an increased probability of being a (heavy) smoker and a decreased ability to quit smoking. The study cohort consisted of all subjects in the Rotterdam Study, a Dutch population-based cohort of people aged 55 years and older, for whom BclI genotyping and smoking status at baseline were available. In prospective analyses, the smoking status was reassessed during three additional examination rounds. Logistic regression analysis was used to study the association between BclI polymorphism and being a smoker or a heavy smoker at baseline. Furthermore, the relationship between BclI polymorphism and incident smoking cessation was tested with Cox proportional hazards analysis within those who smoked at baseline. In total, 6358 subjects were included in the study. The presence of a G-allele was not associated with current smoking at baseline [odds ratio (OR) = 0.96, 95%confidence interval (CI): 0.85,1.09] or with the incidence of smoking cessation during follow-up [hazard ratio (HR) = 0.98, 95%CI: 0.80,1.19]. Within current smokers, having a G-allele was not significantly associated with the risk of being a heavy smoker when measured by pack-years smoked (OR = 1.07, 95%CI: 0.85,1.35) or daily consumption of tobacco (OR = 1.10, 95%CI: 0.88,1.37). We were not able to replicate the earlier findings indicating that the proportion of current smokers is lower among carriers of the CC-genotype of the BclI glucocorticoid receptor. Furthermore, the BclI glucocorticoid receptor polymorphism did not predict the incidence of smoking cessation in the general elderly population. [source] Glucocorticoid resistance in a multiple myeloma cell line is regulated by a transcription elongation block in the glucocorticoid receptor gene (NR3C1)BRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2009Beatriz Sánchez-Vega Summary Glucocorticoid (GC) effects are mediated by the glucocorticoid receptor (GR). Several studies have demonstrated that a lower number of receptors per cell were associated with poor GC response. The regulation of GR expression is complex; the levels of GR can be autologously regulated by its ligand and also by transcriptional, post-transcriptional and post-translational mechanisms. Using three human myeloma cell lines that parallel the development of GC resistance, this work describes the mechanism involved in the downregulation of GR expression. The decreased expression was neither due to mutations in the gene encoding GR, NR3C1, nor due to methylation of the promoters. A gradual decrease in NR3C1 transcripts was seen during the development of resistance, the level of expression of exon 1 to 2 RNA fragments remained the same in sensitive and resistant cell lines but a chromatin immunoprecipitation assay demonstrated that RNA polymerase II, detectable throughout exon 2 to 3 in the sensitive cells, was undetectable on exon 3 in the resistant variant, suggesting lower or no transcription at this site. These studies demonstrated that downregulation of NR3C1 mRNA in a resistant cell line involves a block to transcriptional elongation within intron B of NR3C1. This block may represent an important element in the regulation of GR expression. [source] The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patientsCLINICAL ENDOCRINOLOGY, Issue 1 2003Anna Maria Di Blasio Summary objective ,We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low-dose dexamethasone (0·25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a BclI restriction site polymorphism in a group of Italian patients with severe obesity. design Two hundred and seventy-nine patients (mean BMI 45·9 ± 0·9 kg/m2) were genotyped using both PCR-restriction fragment length polymorphism analysis and Taqman Sequence Detection System. Determination of several metabolic and antropometric parameters was also performed in order to correlate them to the genotype. results In this group of obese patients, 13 subjects (eight female, five males) were heterozygous for the N363S variant (allelic frequency 2·3%) and had significantly higher BMI (P < 0·04), resting energy expenditure (P < 0·03) and food intake (P < 0·01) when compared to wild-type homozygotes. When the data were analysed according to sex, female heterozygotes for the N363S allele had significantly higher BMI (P = 0·04), resting energy expenditure (P = 0·03) and food intake (P = 0·008) than obese women with the wild-type 363 GR gene. Male carriers of this variant also had higher values for these variables although the differences did not reach statistical significance. A case,control study with homozygous wild-type obese subjects which were age-, sex- and BMI-matched, revealed no difference in resting energy expenditure and food intake. The allele frequency of the BclI variant was 27% (89 females and 41 males out of 269 subjects). No differences in anthropometric and metabolic parameters were found between subjects heterozygous or homozygous for this variant GR in this obese population. However, when we studied the effect of the presence of the BclI polymorphism and the N363S variant in the same individual, we found that the subjects who carried both polymorphisms had a tendency towards higher systolic and diastolic blood pressure and significantly higher total and LDL-cholesterol levels (P = 0·005 and P = 0·05, respectively). discussion Taking the results of this study and those obtained in the Dutch population, we speculate that heterozygous carriers of the N363S variant who develop obesity, may become even more obese, possibly because they have a hypersensitive insulin response and thus, via activation of lipogenesis, store fat more efficiently. Furthermore, these data suggest that N363S carriers who carry the BclI polymorphism as well, tend to have a slightly unfavourable cardiovascular profile. [source] Examining the Intersection of Sex and Stress in Modelling Neuropsychiatric DisordersJOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2009N. Goel Sex-biased neuropsychiatric disorders, including major depressive disorder and schizophrenia, are the major cause of disability in the developed world. Elevated stress sensitivity has been proposed as a key underlying factor in disease onset. Sex differences in stress sensitivity are associated with corticotrophin-releasing factor (CRF) and serotonin neurotransmission, which are important central regulators of mood and coping responses. To elucidate the underlying neurobiology of stress-related disease predisposition, it is critical to develop appropriate animal models of stress pathway dysregulation. Furthermore, the inclusion of sex difference comparisons in stress responsive behaviours, physiology and central stress pathway maturation in these models is essential. Recent studies by our laboratory and others have begun to investigate the intersection of stress and sex where the development of mouse models of stress pathway dysregulation via prenatal stress experience or early-life manipulations has provided insight into points of developmental vulnerability. In addition, examination of the maturation of these pathways, including the functional importance of the organisational and activational effects of gonadal hormones on stress responsivity, is essential for determination of when sex differences in stress sensitivity may begin. In such studies, we have detected distinct sex differences in stress coping strategies where activational effects of testosterone produced females that displayed male-like strategies in tests of passive coping, but were similar to females in tests of active coping. In a second model of elevated stress sensitivity, male mice experiencing prenatal stress early in gestation showed feminised physiological and behavioural stress responses, and were highly sensitive to a low dose of selective serotonin reuptake inhibitors. Analyses of expression and epigenetic patterns revealed changes in CRF and glucocorticoid receptor genes in these mice. Mechanistically, stress early in pregnancy produced a significant sex-dependent effect on placental gene expression that was supportive of altered foetal transport of key growth factors and nutrients. These mouse models examining alterations and hormonal effects on development of stress pathways provide necessary insight into how specific stress responses can be reprogrammed early in development resulting in sex differences in stress sensitivity and neuropsychiatric disease vulnerability. [source] | ||||||||||