Glucocorticoid Receptor Polymorphisms Research Articles

Glucocorticoid Receptor Polymorphism A3669G Is Associated with Airflow Obstruction in Mild-to-Severe Asthma

Background: Glucocorticoids (GCs) represent the mainstay therapy for asthmatics. A subset of severe asthmatics fails to respond to steroid-based therapies, leading to important healthcare costs. Single nucleotide polymorphisms (SNPs) of glucocorticoid receptor genes were associated with a response to GC. We evaluate the possible relation of BclI and A3669G SNPs to clinical, biological and functional characteristics of asthmatics. Methods: We recruited 172 mild-to-severe asthmatic outpatients referring to the Severe Asthma and Rare Lung Disease Unit at San Luigi University Hospital. Clinical data were obtained at recruitment when spirometry tests and peripheral blood sampling were performed. Patients were genotyped for BclI and A3669G through the pyrosequencing assay results. Results: Patients with the A3669G AG genotype were younger, allergic and had higher IgE levels compared to AA genotype (p < 0.05). Moreover, asthmatics with the AA genotype had a lower post-bronchodilator FEV1/FVC ratio than the GG genotype (p < 0.05), and a higher RV/TLC ratio than the AG genotype (p < 0.05). Conclusions: The A3669G AG genotype might be related to type-2 allergic asthma; in particular, allele A of A3669G SNP was associated with GC response in our asthmatics. In conclusion, this observational cross-sectional study suggests a possible role of A3669G SNP as a predictor of asthma severity and phenotype.

Effects of prenatal exposure to the 1944–45 Dutch famine and glucocorticoid receptor polymorphisms on later life PTSD susceptibility

ABSTRACT Background: Exposure to adversity in utero is thought to increase susceptibility to develop posttraumatic stress disorder (PTSD) following later life trauma, due to neurobiological programming effects during critical developmental periods. It remains unknown whether effects of prenatal adversity on PTSD susceptibility are modulated by genetic variations in neurobiological pathways implicated in PTSD susceptibility. Objective: We investigated whether genetic variation in the glucocorticoid receptor (GR) modulated effects of prenatal famine exposure on late adulthood PTSD symptom severity after trauma exposure in childhood and mid-to-late adulthood. Method: We included N = 439 term-born singleton adults (mean age: 72 years, 54.2% women) from the Dutch Famine Birth Cohort, born around the time of the Dutch Famine of 1944/1945, divided into exposure and control groups based on timing of the famine during gestation. Participants filled out self-report questionnaires on childhood (Childhood Trauma Questionnaire) and mid-to-late adulthood (Life Events Checklist for DSM-5) trauma, and current PTSD symptom severity (PTSD Checklist for DSM-5). GR haplotypes were determined from four functional GR single nucleotide polymorphisms (ER22/23EK, N363S, BclI and exon 9β) in previously collected DNA. Linear regression analyses were performed to investigate associations of GR haplotype and prenatal famine exposure in conjunction with later life trauma on PTSD symptom severity. Results: We observed a significant three-way interaction between the GR Bcll haplotype, famine exposure during early gestation, and adulthood trauma exposure on PTSD symptom severity in late adulthood. Only participants exposed to famine during early gestation without the GR Bcll haplotype showed a significantly stronger positive association between adulthood trauma and PTSD symptom severity than non-exposed participants, indicating increased PTSD susceptibility. Conclusions: Our results illustrate the importance of integrated approaches considering genetics and environmental contexts throughout various life periods, including the rarely investigated prenatal environment, to elucidate how PTSD susceptibility evolves throughout life. HIGHLIGHTS Adversity during pregnancy is thought to increase offspring’s PTSD risk following later life trauma, but exact neurobiological mechanisms underlying this process remain unknown. We found that effects of prenatal famine exposure on PTSD symptom severity were influenced by genetic variation in the glucocorticoid receptor, which signals effects of the stress hormone cortisol. Integrated approaches considering genetics and environmental contexts throughout both early and later life are important to understand how PTSD risk evolves throughout life.

Glucocorticoid receptor polymorphism BclI with increased glucocorticoid sensitivity has a positive influence on quality of life in endogenous Cushing's syndrome in remission.

Patients with endogenous Cushing's syndrome (CS) may suffer from a wide range of neuropsychiatric symptoms leading to impaired quality of life (QoL). Glucocorticoid receptor (GR) polymorphisms are associated with increased (BclI and N363S) or decreased (A3669G and ER22/23EK) GR sensitivity. GR genotypes may modulate and affect QoL and recovery after remission differently via GR sensitivity. 295 patients with endogenous CS (81 active, 214 in remission) from 3 centers of the German Cushing's Registry were included for the cross-sectional analysis. All subjects were assessed with three questionnaires (CushingQoL, Tuebingen CD-25, SF-36). For the longitudinal part, 120 patients of them were analyzed at baseline and after 1.5 ± 0.9 yrs of follow-up. DNA samples were obtained from peripheral blood leukocytes for GR genotyping. Patients in remission scored significantly better than patients with active CS in the CushingQoL questionnaire and in the SF-36 sub-categories physical and social functioning, role-physical, bodily pain, and vitality. In cross-sectional analysis, no differences in QoL between minor allele and wildtype carriers were detected for all polymorphisms in active or cured CS. In longitudinal analysis, however, carriers with BclI minor allele showed significant improvement in SF-36 sub-categories vitality (P = .038) and mental health (P = .013) compared to wildtype carriers (active CS at baseline vs. CS in remission at follow-up). The outcome of the two questionnaires CushingQoL and Tuebingen CD-25 improved significantly in both wildtype and minor allele carriers. BclI minor allele carriers initially had the lowest QoL but recovered better from impaired QoL than wildtype carriers.

Genetic polymorphisms of glucocorticoid receptor and their association with new-onset diabetes mellitus in kidney transplant recipients

IntroductionThe variability in developing New-onset Diabetes Mellitus After Transplantation (NODAT), together with previously well-established interindividual variation in glucocorticoid sensitivity, led us to hypothesize that polymorphisms in the NR3C1 gene encoding glucocorticoid receptor may alter glucose balance in kidney transplant recipients. This study aimed to evaluate the association of three functional polymorphisms, BclI, N363S, and ER22/23EK, on the NR3C1 gene with NODAT in kidney allograft recipients. MethodsFrom Jun 2020 to July 2022 in Shiraz, 52 patients with NODAT (case group) and 52 non-diabetic kidney transplant recipients (control group) were randomly screened and recruited in this case-control study. The PCR-RFLP technique determined the genotypes of BclI, N363S, and ER22/23EK polymorphisms. ResultsThe allelic frequencies of the mutant alleles of BclI, N363S, and ER22/23EK polymorphisms in all patients were 0.36, 0.03, and 0.009, respectively. BclI mutant genotypes (CG and GG) were significantly associated with an increased risk of NODAT (P = 0.016), while the two other polymorphisms disclosed no significant association with NODAT development. In the case group, no significant association was detected between the onset time of NODAT and studied polymorphisms, including BclI (P = 0.43), N363S (P = 0.30), and ER22/23EK. P value was not reported for the last polymorphism because all patients with NODAT had the wild-type genotype (GG/GG) and performing statistical analysis was not feasible. Among studied demographic/clinical/paraclinical variables, factors such as higher mean trough level of tacrolimus during the first month after transplantation and higher mean daily dose of prednisolone significantly linked with NODAT development. ConclusionOur data suggested that BclI polymorphism significantly affects NODAT development among Iranian kidney allograft recipients.

Adrenalectomy Improves Blood Pressure and Metabolic Control in Patients With Possible Autonomous Cortisol Secretion: Results of a RCT.

ObjectiveThe best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the metabolic effect of adrenalectomy in AI patients with PACS in relation to cortisol secretion parameters, peripheral activation, and glucocorticoid sensitivity.DesignThis is a multicenter randomized study (NCT number: NCT04860180).MethodsSixty-two AI outpatients (40–75 years) with AI >1 cm and cortisol after overnight dexamethasone suppression test (F-1mgDST) between 50 and 138 nmol/L were randomized to adrenalectomy (Arm A) or a conservative approach (Arm B). Fifty-five patients completed the 6-month follow-up, 25 patients in Arm A (17 female patients, aged 62.5 ± 10.4 years) and 30 patients in Arm B (24 female patients, 66.1 ± 9.1 years). Plasma adrenocorticotroph hormone (ACTH), 24-h urinary free cortisol, 24-h urinary free cortisone, F-1mgDST, glucose, lipids, glycated hemoglobin (HbA1c) levels, blood pressure (BP), body weight, and treatment variations were assessed. The 24-h urinary free cortisol/cortisone ratio (an 11-beta hydroxysteroid dehydrogenase type 2 activity marker), BclI, and the N363S variants of glucocorticoid receptor (GR) polymorphisms were also evaluated.ResultsBP control improved in 68% and 13% of the subjects in Arm A and Arm B, respectively (p = 0.001), and the glycometabolic control improved in 28% and 3.3% of the subjects in Arm A and Arm B patients, respectively (p = 0.02). Arm A subjects more rarely showed the BP and/or glycometabolic control worsening than Arm B patients (12% and 40%, respectively, p = 0.03). The surgical approach was independently associated with BP amelioration (OR 3.0, 95% CI 3.8–108.3, p < 0.001) but not with age, F-1mgDST levels, BMI, and hypertension and diabetes mellitus presence at baseline. The 24-h urinary free cortisol/cortisone ratio and the presence of sensitizing GR polymorphisms were not associated with the surgical outcome. The receiver operating characteristic (ROC) curve analysis showed that the BP control amelioration was associated with F-1mgDST [area under the curve (AUC), 0.82 ± 0.09 p = 0.012]. The F-1mgDST cutoff with the best compromise in predicting the BP amelioration was set at 75 nmol/L (sensitivity 77%, specificity 75%).ConclusionsAI patients with PACS benefit from surgery in terms of BP and glycometabolic control.

Genetic Profiling of Glucocorticoid (NR3C1) and Mineralocorticoid (NR3C2) Receptor Polymorphisms before Starting Therapy with Androgen Receptor Inhibitors: A Study of a Patient Who Developed Toxic Myocarditis after Enzalutamide Treatment.

Enzalutamide is a nonsteroidal inhibitor of the androgen receptor (AR) signaling pathway and is used to treat patients with metastatic castration-resistant prostate cancer. However, the risk of cardiovascular-related hospitalization in patients with no contraindications for the use of enzalutamide is about 1–2%. To date, the underlying molecular basis of this has not been established. The androgen receptor, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are nuclear receptors that share structural similarities and have closely related DNA-binding sites and coregulators. In non-epithelial cells, a fine balance of the activities of these receptors is essential to ensure correct cellular function. In this study, we present a molecular characterization of these nuclear receptors in a prostate cancer patient who developed congestive heart failure after enzalutamide treatment. White cell RNAseq revealed a homozygous rs5522 MR polymorphism and both the rs143711342 and rs56149945 GR polymorphisms, carried in different alleles. No different specific splice isoforms were detected. Recent research suggests that AR inhibition by enzalutamide makes available a coregulator that specifically interacts with the rs5522-mutated MR, increasing its activity and producing adverse effects on cardiovascular health. We suggest an evaluation of the MR rs5522 polymorphism before starting therapy with AR inhibitors.

Analysis of the body composition and glucose metabolism in relation to bcli glucocorticoid receptor polymorphism in women with adrenal incidentalomas

Analysis of the body composition and glucose metabolism in relation to bcli glucocorticoid receptor polymorphism in women with adrenal incidentalomas

Adrenal suppression in patients with chronic obstructive pulmonary disease treated with glucocorticoids: Role of specific glucocorticoid receptor polymorphisms.

Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids, and thus may alter the therapeutic effects of glucocorticoids. We investigated the prevalence of adrenal suppression after treatment with glucocorticoids and evaluated whether GR SNPs were associated with altered risks of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD). In an observational prospective cohort study, we recruited 78 patients with severe COPD receiving 5 days glucocorticoid treatment for an exacerbation of COPD. In total, 55% of these patients were also receiving regular inhaled corticosteroids (ICS). Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK, and 9β SNPs. The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 30 days after glucocorticoid treatment was 4/78 (5%). There was no difference between carriers and non-carriers of the polymorphisms (Bcl1, 9β, ER22/23K, and N363S) in corticotropin stimulated plasma-cortisol concentrations. In the haplotype analyses, we included the 50 patients who had a high-sensitivity (76%), a low-sensitivity (4%), or a wild-type (20%) GR haplotype. There was no difference in the frequency of adrenal suppression or metabolic disorders between the two stratified groups: (a) high-sensitivity (Bcl1 and/or N363S) haplotypes vs. (b) low-sensitivity (9β and/or ER22/23K) plus wild-type haplotypes (p > 0.05). Carriers of the high-sensitivity GR gene haplotype exhibited a steeper decline in stimulated P-cortisol with increased ICS dose (slope, -1.35 vs. 0.94; p = 0.17), compared to the group with low-sensitivity or wild-type haplotypes, respectively. In total, 5% of patients exhibited insufficient adrenal function. The Bcl1 and N363S polymorphisms did not seem to increase the risk of glucocorticoid suppression or metabolic disorders in adults treated with glucocorticoids for COPD exacerbations.

Glucocorticoid Receptor Signaling in Diabetes.

Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation.

The Glucocorticoid Receptor Polymorphism Landscape in Patients With Diamond Blackfan Anemia Reveals an Association Between Two Clinically Relevant Single Nucleotide Polymorphisms and Time to Diagnosis.

NR3C1, the gene encoding the glucocorticoid receptor, is polymorphic presenting numerous single nucleotide polymorphisms (SNPs) some of which are emerging as leading cause in the variability of manifestation and/or response to glucocorticoids in human diseases. Since 60–80% of patients with Diamond Blackfan anemia (DBA), an inherited pure red cell aplasia induced by mutations in ribosomal protein genes became transfusion independent upon treatment with glucocorticoids, we investigated whether clinically relevant NR3C1 SNPs are associated with disease manifestation in DBA. The eight SNPs rs10482605, rs10482616, rs7701443, rs6189/rs6190, rs860457, rs6198, rs6196, and rs33388/rs33389 were investigated in a cohort of 91 European DBA patients. Results were compared with those observed in healthy volunteers (n=37) or present in public genome databases of Italian and European populations. Although, cases vs. control analyses suggest that the frequency of some of the minor alleles is significantly altered in DBA patients with respect to healthy controls or to the Italian or other European registries, lack of consistency among the associations across different sets suggests that overall the frequency of these SNPs in DBA is not different from that of the general population. Demographic data (47 females and 31 males) and driver mutations (44 S and 29 L genes and eight no-known mutation) are known for 81 patients while glucocorticoid response is known, respectively, for 81 (36 responsive and 45 non-responsive) and age of disease onsets for 79 (55 before and 24 after 4months of age) patients. Neither gender nor leading mutations were associated with the minor alleles or with disease manifestation. In addition, none of the SNPs met the threshold in the response vs. non-responsive groups. However, two SNPs (rs6196 and rs860457) were enriched in patients manifesting the disease before 4months of age. Although the exact biomechanistical consequences of these SNPs are unknown, the fact that their configuration is consistent with that of regulatory regions suggests that they regulate changes in glucocorticoid response during ontogeny. This hypothesis was supported by phosphoproteomic profiling of erythroid cells expanded ex vivo indicating that glucocorticoids activate a ribosomal signature in cells from cord blood but not in those from adult blood, possibly providing a compensatory mechanism to the driving mutations observed in DBA before birth.

The association of glucocorticoid receptor polymorphism with metabolic outcomes in menopausal women with adrenal incidentalomas

ObjectivesTo investigate whether BclI polymorphism in the glucocorticoid receptor gene influences hypothalamic-pituitary-adrenal (HPA) axis regulation, body composition and metabolic parameters in women with adrenal incidentalomas (AIs). Study designA cross-sectional study. Main outcome measuresWe analyzed 106 women with AIs. Insulin resistance was assessed using a homeostasis model while HPA activity was assessed using dexamethasone suppression tests (DST), basal ACTH, urinary free cortisol, and midnight serum cortisol level. Body composition was analyzed using dual-energy X-ray absorptiometry. DNA was obtained from peripheral blood leucocytes and BclI polymorphism was detected using PCR, RFLP and DNA sequencing. ResultsBclI carriers in comparison with those with wild-type BclI had less suppressed cortisol after DST-0.5 mg (126.4 ± 111.4 vs 80.9 ± 75.7 nmol/l, p = 0.026) and had a lower prevalence of impaired glucose tolerance and of type 2 diabetes mellitus (T2DM). BclI carriers had a higher percentage of leg fat mass (FM), lower left-sided limb muscle mass and a decline in total lean body mass. Duration of menopause remained a strong predictor of appendicular lean mass index (ALMI) (β=-0.125, p = 0.034). BclI polymorphism was significantly associated with sum of legs FM percentage (β=0.327, p = 0.048). T2DM was negatively associated with BclI polymorphism, after adjusting for age, truncal FM, ALMI, and sum of legs FM (OR=0.158, 95%CI 0.031–0.806, p = 0.027). ConclusionsBclI polymorphism is associated with tissue-specific glucocorticoid sensitivity, relative glucocorticoid resistance of the HPA axis and peripheral adipose tissue, and glucocorticoid hypersensitivity at the muscle level. By modulating glucocorticoid and insulin sensitivity, BclI polymorphism appears to reduce the risk of T2DM in women with AIs.

Anthropometrics and Metabolic Syndrome in Relation to Glucocorticoid Receptor Polymorphisms in Corticosteroid Users

Introduction: Corticosteroids are widely prescribed and their use has been linked to adverse cardiometabolic outcomes. A pivotal role in the action of corticosteroids is reserved for the glucocorticoid receptor (GR). Here, we assessed the relationship of glucocorticoid sensitivity-altering GR polymorphisms with anthropometrics and metabolic syndrome (MetS) in corticosteroid users. Methods: In this population-based cohort study (Lifelines), we genotyped 10,621 adult participants for GR hypersensitive (1/2 copies BclI and/or N363S) and GR resistant (1/2 copies ER22/23EK and/or 9β) variants. We assessed the relationship between functional GR polymorphisms with BMI, waist circumference (WC), and MetS in users of corticosteroids. Results: Overall corticosteroid use was associated with a significantly higher BMI and WC in GR wild-type (WT) users (BMI, +0.63 kg/m² [0.09–1.16], p = 0.022; WC, +2.03 cm [0.61–3.44], p = 0.005) and GR hypersensitive (BMI, +0.66 kg/m² [95% CI, 0.31–1.01]; WC, +2.06 cm [1.13–2.98], both p < 0.001) but not in GR resistant users. Significantly higher WC in GR resistant carriers was observed only for inhaled corticosteroid users. With respect to MetS, again only GR WT users (odds ratio [OR] 1.44 [1.07–1.94], p = 0.017) and GR hypersensitives (OR 1.23 [95% CI, 1.00–1.50], p = 0.046) were more likely to have MetS; even more pronounced in only inhaled corticosteroid users (GR WT users, OR 1.64 [1.06–2.55], p = 0.027; GR hypersensitive users, OR 1.43 [1.08–1.91], p = 0.013). Conclusions: Polymorphisms associated with increased GR sensitivity and WT GR are related to increased BMI, WC, and an increased MetS presence in corticosteroid users, especially of the inhaled types, when compared to nonusers. The adverse effects of corticosteroid use are less pronounced in users harboring GR resistant polymorphisms.

Glucocorticoid receptor gene polymorphisms in Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an immune-mediated paralytic disorder. Glucocorticoid receptor (GR) gene polymorphisms affect the sensitivity to glucocorticoids and have been related to microbial colonization and infection, and thereby may influence susceptibility to GBS. The associations between GR polymorphisms (ER22/23EK, N363S, BclI, TthIII-1 and GR-9beta) and development of GBS were investigated in 151 patients and 151 healthy controls. GR polymorphisms or haplotypes were not associated with GBS susceptibility. Haplotype 1 (TthIII-1[T/T]:BclI[G/G]:GR-9beta[A/A]) was less common in GBS; but not statistically significant after correction (P = 0.021; Pc = 0.108). The GR-9beta(G/A) and TthIII-1(C/T) genotypes were frequent in anti-GM1-antibody-positive patients than anti-GM1-antibody-negative patients (P = 0.017 and P = 0.030, respectively).

Association of the subclinical hypercorticism and BclI glucocorticoid receptor polymorphism with bone mineral density in women with adrenal incidentalomas

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Вовлеченность генов гипоталамо-гипофизарно-надпочечниковой системы в формирование индивидуальных различий в уровне стрессовой неустойчивости

Целью настоящего исследования являлась оценка вклада 10 полиморфных локусов генов глюкокортикоидного (NR3C1) и минералокортикоидного (NR3C2) рецепторов, а также ген-средовых (G×E) взаимодействий в формирование межиндивидуальных различий в индивидуальных психологических свойствах у 1215 психически здоровых индивидов. Множественный регрессионный анализ выявил, что пренатальный уровень солнечной активности оказывал модулирующий эффект на ассоциацию функциональных полиморфных локусов rs56149945 (N363S) с показателями по шкале «настойчивость» (β = 1,21; р = 0,001) и rs41423247 в гене NR3C1 с индивидуальными различиями в уровне эмоциональной неустойчивости (β = -2,72; р = 0,005). The present study aimed to assess the main effects of ten polymorphisms of glucocorticoid (NR3C1) and mineralocorticoid receptor (NR3C2) genes together with gene-by-environment interactions on individual differences in personality traits in 1215 mentally healthy individuals aged 17-25 years. Multiple linear regression analysis demonstrated that prenatal solar activity level modulated the association of rs56149945 (N363S) with Persistence (β = 1.21; Р = 0.001) and rs41423247 in NR3C1 gene with emotional resistance to stress (β = -2.72; Р = 0.005).

Glucocorticoid Receptor Polymorphisms in Children Undergoing Congenital Heart Surgery with Cardiopulmonary Bypass.

We conducted a candidate gene association study to test the hypothesis that different gene polymorphisms will be associated with corticosteroid responsiveness and study outcomes among children undergoing congenital heart surgery. This is a prospective observational cohort study at a large, tertiary pediatric cardiac center on children undergoing corrective or palliative congenital heart surgery. A total of 83 children were enrolled. DNA was isolated for three polymorphisms of interest namely N363 (rs56149945) and 9β (rs6198) associated with increased sensitivity to corticosteroids and Bcl I (rs41423247) associated with decreased sensitivity to corticosteroids. Duration of inotropic use, low cardiac output scores (LCOS), and vasoactive inotrope scores were examined in relation to these three polymorphisms. Using Kaplan-Meier analysis, heterozygous individuals showed longer transcriptional intermediary factor (TIF) compared with wild type for N363 polymorphism ( p = 0.05). In multivariable Cox regression, heterozygous alleles for 9β polymorphism showed significantly shorter TIF compared with wild type (hazard ratio = 2.04 [1.08-3.87], p = 0.03). The relationship between lower LCOS scores and alleles groups was significant for 9β heterozygous polymorphism only (1.5 [1-2.2], p = 0.01) in comparison to wild type and homozygous. The presence of heterozygote alleles for the increased corticosteroid sensitivity is associated with longer TIF compared with wild type. Conversely, the presence of heterozygous alleles for the decreased sensitivity to corticosteroids is associated with shorter TIF compared with wild type.

Serum cortisone and glucocorticoid receptor gene (NR3C1) polymorphism in human dysglycemia.

We aimed to explore the associations of serum cortisone and glucocorticoid receptor (GR) polymorphism with glucose metabolism and type 2 diabetes mellitus (T2DM) among Chinese adults. A total of 2315 participants were included in the present study. Serum cortisone was measured by liquid chromatography-tandem mass spectrometry. Multivariable logistic regression and linear regression were employed to assess the associations between serum cortisone and different glucose metabolism status. Serum cortisone was positively associated with impaired fasting glucose (IFG) and T2DM ((Quartile 4 vs Quartile 1, odds ratio (OR) = 1.36, 95% confidence interval (CI) 1.01, 1.84, and OR = 2.08, 95% CI 1.50, 2.89, respectively)). A 100% increase in cortisone was associated with a 0.015 (95% CI 0.005, 0.025) mg/dl higher fasting plasma glucose (FPG), a 0.007 (95% CI 0.001, 0.013) higher glycosylated hemoglobin (HbA1c), a 0.4% (95% CI - 0.007, 0.000) lower HOMA2-IR, and a 58.1% (95% CI - 0.788, - 0.373) lower HOMA2-β. After stratification by genotype, the association between serum cortisone and T2DM was not significant in TT genotype carriers. In addition, at the higher concentrations of cortisone, TT genotype carriers had a lower FPG, HbA1c, and HOMA2-IR and a higher HOMA2-β than GG and GT carriers. Elevated serum cortisone was associated with an increased risk of IFG and T2DM, and the associations may be modified by rs9324924 polymorphism.

Glucocorticoid Receptor Polymorphisms Influence Muscle Strength in Cushing's Syndrome.

An important clinical feature of Cushing's syndrome (CS) is proximal muscle myopathy caused by glucocorticoid induced protein metabolism. However, interindividual differences cannot be explained solely by the pure extent of hypercortisolemia. To evaluate the effects of glucocorticoid receptor (GR) polymorphisms (BclI, N363S, ER22/23EK and A3669G), which influence peripheral glucocorticoid sensitivity on muscular function in endogenous CS. 205 patients with proven endogenous CS (128 central, 77 adrenal) from 3 centers of the German Cushing's Registry and 125 subjects, in whom CS was ruled out, were included. All subjects were assessed for grip strength (via hand grip dynamometer) and performed a chair-rising test (CRT). DNA samples were obtained from peripheral blood leukocytes for GR genotyping. In patients with active CS, normalized handgrip strength of the dominant and nondominant hand was higher in A3669G minor allele than in wildtype carriers (P = .006 and P = .021, respectively). CS patients in remission and ruled-out CS showed no differences in handgrip strength regarding A3669G minor allele and wildtype carriers. Male CS patients harboring the ER22/23EK wildtype presented lower hand grip strength than minor allele carriers (P = .049 dominant hand; P = .027 nondominant hand). The other polymorphisms did not influence handgrip strength. CRT showed no differences regarding GR polymorphisms carrier status. Handgrip strength seems to be more susceptible to hypercortisolism in A3669G wildtype than in A3669G minor allele carriers. This might partially explain the inter-individual differences of glucocorticoid-induced myopathy in patients with endogenous CS. ER22/23EK polymorphism seems to exert sex-specific differences.

Association of the BclI glucocorticoid receptor polymorphism with body composition and metabolic parameters in female patients with adrenal incidentalomas

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Interactive influence of sex, stressor timing, and the BclI glucocorticoid receptor polymorphism on stress-induced alterations of long-term memory

Certain susceptibility factors, such as genetic variants or specific physiological responses to stress, can dictate the effects of stress on learning and memory. Here, we examined the influence of the BclI polymorphism of the glucocorticoid receptor gene on the time-dependent effects of pre-learning stress on long-term memory. Healthy individuals were exposed to the socially evaluated cold pressor test or a control condition immediately or 30 min before word list learning. Participants’ memory for the words was tested immediately and 24 h after learning, and saliva samples were collected to genotype participants for the BclI polymorphism and to assess cortisol responses to the stressor. Results revealed that stress immediately before learning enhanced memory, while stress 30 min before learning impaired memory; these effects were largely selective to males and non-arousing words. Additionally, stress, independent of when it was administered, enhanced memory in non-carriers of the BclI polymorphism, while impairing memory in carriers; these effects were largely selective to males and participants exhibiting a robust cortisol response to stress. These results provide further evidence for time-dependent effects of stress on long-term memory and suggest that carriers of the BclI polymorphism might be more sensitive to the negative effects of corticosteroids on learning.