Glucocorticoid Receptor Gene Polymorphisms Research Articles

Urinary leukotriene and Bcl I polymorphism of glucocorticoid receptor gene in preschoolers with recurrent wheezing and high risk of asthma

BackgroundUrinary leukotriene (LTE4) is an important marker of airway inflammation presence. A relationship between single nucleotide polymorphism in the glucocorticoid receptor (GCR) gene promoter (Bcl I polymorphism), development of asthma and sensitivity to glucocorticoids has been hypothesised. ObjectiveTo explore the possible association between the Bcl I polymorphism and baseline levels of urinary LTE4 in preschoolers with recurrent wheezing episodes. We prospectively enrolled and classified 86 preschoolers based on the risk of developing asthma (by the Asthma Predictive Index [API]). MethodsAt admission standardised questionnaires for demographics and respiratory illness characteristics were completed. The Bcl I polymorphism of the GCR was determined by a PCR–RFLP assay from blood samples, and urinary leukotriene was assessed from urine samples by an enzyme immunoassay. ResultsWe enrolled 86 preschoolers (46 with positive API and 40 with negative API). There were no statistical differences in demographic, respiratory illnesses and wheezing episodes characteristics between both groups. Also, the prevalence of Bcl I polymorphism was similar between positive vs. negative API groups (34.8% vs. 38.9% for homozygote GG, 56.5% vs. 52.8% for heterozygote GC, 8.7% vs. 8.3% for homozygote CC, respectively, p=0.94). However, urinary LTE4 (median [IQR]) was higher in preschoolers with positive than negative API (7.18 [5.57–8.96pg/ml] vs. 6.42 [3.96–8.07pg/ml], p=0.02, respectively). ConclusionsIn our population, wheezing preschoolers with positive API exhibit higher levels of urinary LTE4 than those with negative API; but there were no differences in Bcl I polymorphism of the GCR.

Glucocorticoid receptor and HSD11B1 gene polymorphisms influence the therapy and therapy-associated morbidities in patients with Addison's disease

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

Glucocorticoid and mineralocorticoid receptor polymorphisms and recurrence of major depressive disorder

Previous research found that variants of the glucocorticoid receptor (GR) (9β, 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. 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. GR and MR gene polymorphisms and derived haplotypes were not associated with recurrence of depression in both retrospective and prospective analyses. In addition, no consistent interactions between GR and MR polymorphisms and childhood trauma or life events were found. This study did not find consistent associations between GR and MR gene polymorphisms, interactions between GR and MR haplotypes and stressful conditions and recurrence of MDD.

Clinical relevance of the glucocorticoid receptor gene polymorphisms in glucocorticoid-induced ocular hypertension and primary open angle glaucoma.

To avoid the side effects of ocular hypertension of glucocorticoid (GC) usage in eye, we must identify susceptible individuals, which exists in about one-third of all population. Further, the majority of all primary open angle glaucoma (POAG) patients show this phenotype. Glucocorticoid receptor (GR) regulates C responsiveness in trabecular meshwork (TM) cells. In this study, single nucleotide polymorphism (SNP) genotyping was used to determine whether there are differences in the BclI (rs41423247) and N363S (rs6195) polymorphisms of the GR gene in healthy and POAG patients, and glucocorticoid-induced ocular hypertension (GIOH) populations. Three hundred and twenty-seven unrelated Chinese adults, including 111 normal controls, 117 GIOH subjects and 99 POAG patients, were recruited. DNA samples were prepared and the BclI and N363S polymorphisms were screened using real-time polymerase chain reaction (RT-PCR)-restriction fragment length polymorphism (RFLP) analysis. Frequencies of the BclI and N363S polymorphisms were determined and compared using Fisher's exact test and the Chi-squared test. Only the BclI polymorphism was identified in the Chinese Han population. The frequency of the G allele was 21.6 % in normal controls, 18.3% in GIOH patients, and 13.64% in the POAG patients. There was no significant difference in polymorphism or allele frequency in the 3 groups. Furthermore, no N363S polymorphism was found in the study subjects. The BclI polymorphisms in GR gene had no association with GIOH and POAG patients, and N363S polymorphism might not exist in the Chinese Han population. Therefore, the BclI polymorphism might not be responsible for the development of GC-induced ocular hypertension or POAG.

The NR3C1 Glucocorticoid Receptor Gene Polymorphisms May Modulate the TGF-beta mRNA Expression in Asthma Patients.

Glucocorticosteroids (GCs) are basic drugs in therapy of a number of diseases, including chronic diseases of the respiratory system. They are the most important anti-inflammatory drugs in the treatment of asthma. GCs after binding to the glucocorticoid receptor (GR) form the complex (transcription factor), which acts on promoter and regulatory parts of genes enhancing the expression of anti-inflammatory proteins and decreasing the proinflammatory protein synthesis, including numerous cytokines mediating inflammation in the course of asthma. Non-sensitivity or resistance to GCs favours an increase in the TGF-β expression. This cytokine plays a central role in asthma inducing fibroblast differentiation and extracellular matrix synthesis. TGF-β isoforms, 1, 2 and 3, are located on chromosome 19q13, 1q41 and 14q24, respectively. GCs reduce TGF-β 1 and TGF-β 2 production and significantly decrease the expression of upregulated TGF-β 1 and TGF-β 2 mRNA induced by exogenous TGF-β. In asthma, TGF-β may play a role in the development of the peribronchiolar and subepithelial fibrosis, which contributes to a significant clinical exacerbation of asthma. Therefore, it is possible that NR3C1 glucocorticoid receptor gene polymorphisms could exert varied effects on the TGF-β mRNA expression and fibrotic process in lungs of asthmatic patients. The aim of the study was to evaluate the impact of polymorphic forms (Tth111I, BclI, ER22/23EK, N363S) of the NR3C1 gene on the level of the TGF-β 1 mRNA expression. A total of 173 patients with asthma and 163 healthy volunteers participated in the study. Genotyping of Tth111I, BclI, ER22/23EK, and N363S polymorphisms of the NR3C1 gene was performed by using PCR-HRM and PCR-RFLP techniques. TGF-β mRNA was assessed by real time RT-PCR. Tth111I SNP significantly (p = 0.0115) correlated with the TGF-β 1 mRNA expression level. The significance of AA and GG genotypes of Tth111I SNP in increasing and decreasing the level of the TGF-β 1 mRNA expression was demonstrated. Both BclI SNP and ER22/23EK SNP did not affect the expression level of the cytokine analysed. The N363S SNP AA genotype of NR3C1 gene statistically significantly influenced the increase in the level of the TGF-β 1 mRNA expression. Thus, SNPs of NR3C1 gene play an important regulatory function in the bronchi of patients suffering from asthma. In the case of the occurrence of Tth111I and N363S polymorphic forms of the gene studied, a reduced ability of GCs to inhibit the TGF-β 1 expression can be observed.

Influence of glucocorticoid receptor gene NR3C1 646 C>G polymorphism on glucocorticoid resistance in asthmatics: a preliminary study.

BackgroundGlucocorticoid receptor gene polymorphism (NR3C1 646 C>G) may play an important role in the development of severe bronchial asthma and resistance to glucocorticoids (GCs).ObjectiveThe aim of the present study was to determine the relation between the 646 C>G polymorphism of the glucocorticoid receptor gene (NR3C1) and resistance to GCs with development of severe bronchial asthma.Material and methodsThis case-control study included 40 patients with severe bronchial asthma and 20 apparently healthy controls. Atopic status was determined by skin prick test reaction to the most common locally-encountered allergens. GCs reversibility test was performed to differentiate between GCs sensitive and GCs resistant asthma. For all subjects, analysis of the glucocorticoid receptor gene polymorphism (NR3C1 646 C>G) was done using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP).ResultsThe frequencies of NR3C1 646 C>G genotypes and alleles differed significantly between asthmatic patients and controls. The frequencies of the CC genotype and C allele carriers were significantly higher among asthmatics than among controls, and also among GCs sensitive asthmatics than among GCs resistant asthmatics. However, NR3C1 646 C>G genotypes and alleles frequencies did not differ significantly according to the atopic status in asthmatics.ConclusionsThe too small sized of the investigated groups is a shortcoming of this study. Nevertheless, the observed variations demonstrate a marked association of NR3C1 646 C>G CC genotype with the development of bronchial asthma and a higher frequency of the C allele among GCs sensitive asthmatics. Large-scale studies are required to investigate the association between polymorphisms of the NR3C1 gene and GCs resistance among asthmatic patients.

The relationship between glucocorticoid receptor polymorphisms, stressful life events, social support, and post-traumatic stress disorder.

BackgroundIt is debatable whether or not glucocorticoid receptor (GR) polymorphisms moderate susceptibility to PTSD. Our objective was to examine the effects of stressful life events, social support, GR genotypes, and gene-environment interactions on the etiology of PTSD.MethodsThree tag single nucleotide polymorphisms, trauma events, stressful life events, and social support were assessed in 460 patients with PTSD and 1158 control subjects from a Chinese Han population. Gene–environment interactions were analyzed by generalized multifactor dimensionality reduction (GMDR).ResultsVariation in GR at rs41423247 and rs258747, stressful life events, social support, and the number of traumatic events were each separately associated with the risk for PTSD. A gene–environment interaction among the polymorphisms, rs41423247 and rs258747, the number of traumatic events, stressful life events, and social support resulted in an increased risk for PTSD. High-risk individuals (a large number of traumatic events, G allele of rs258747 and rs41423247, high level stressful life events, and low social support) had a 3.26-fold increased risk of developing PTSD compared to low-risk individuals. The association was statistically significant in the sub-groups with and without childhood trauma.ConclusionsOur data support the notion that stressful life events, the number of trauma events, and social support may play a contributing role in the risk for PTSD by interacting with GR gene polymorphisms.

Role of clinical risk factors and polymorphisms in glucocorticoid receptor gene in the determining the risk of developing new-onset diabetes after kidney transplantation

Role of clinical risk factors and polymorphisms in glucocorticoid receptor gene in the determining the risk of developing new-onset diabetes after kidney transplantation

Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome

OBJECTIVES:We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome.METHOD:Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests.RESULTS:Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects.CONCLUSION:The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment.

Hypothalamic–pituitary–adrenal axis activity, personality traits, and BCL1 and N363S polymorphisms of the glucocorticoid receptor gene in metabolically obese normal-weight women

We sought associations among metabolic profiles, copeptin levels, emotional control, personality traits, and hypothalamic–pituitary–adrenal axis activity in metabolically obese normal-weight young women (MONW). We assessed body composition, including fat-free mass; body fat (BF) and android and gynoid fat depots; fasting blood glucose, insulin, copeptin, cortisol (baseline and after dexamethasone), adrenocorticotropin (ACTH), triglycerides, total cholesterol, low- (LDL) and high-density (HDL) lipoproteins; and the BCL1 and N363S polymorphisms of the glucocorticoid receptor gene in 59 MONW and 71 healthy women aged 20–40 years. We also evaluated personality traits using the NEO-Five Factor Inventory and the subjective extent of emotional suppression by the Courtauld Emotional Control Scale. Compared to the controls, MONW had significantly higher insulin, cholesterol, LDL, triglycerides, and waist circumference, but lower HDL. MONW also had increased BF (>30 % of weight) and unfavorable regional fat distribution with excess android fat. The android/BF ratio was 8.29 % (MONW) versus 7.89 % (controls) (p = 0.005), while the gynoid/BF ratio was 31.99 versus 34.1 %, respectively (p = 0.008). Despite similar ACTH levels in both groups, MONW had higher cortisol levels both at the baseline (p < 0.001) and in the dexamethasone suppression test (p = 0.003). Copeptin levels and the distribution of glucocorticoid receptor polymorphisms were similar in both groups. There were also no significant differences in psychological features between MONW and controls. In conclusion, the MONW phenotype was associated with hypothalamic–pituitary–adrenal axis dysregulation, unfavorable metabolic profiles, and fat accumulation, but normal distribution of glucocorticoid receptor gene polymorphisms and copeptin levels, and no significant differences in psychological features between MONW and controls.

Influence of the A3669G Glucocorticoid Receptor Gene Polymorphism on the Metabolic Profile of Pediatric Patients with Congenital Adrenal Hyperplasia.

Background. Pediatric CAH patients have an increased risk of cardiovascular disease, and it remains unknown if genetic predisposition is a contributing factor. Glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of pediatric CAH patients. Methods. Forty-one patients (26SW/15SV) received glucocorticoid (GC) replacement therapy to achieve normal androgen levels. Obesity was defined by BMI ≥ 95th percentile. NR3C1 alleles were genotyped, and association analyses with phenotype were done with Chi-square, t-test, and multivariate and regression analysis. Results. Obesity was observed in 31.7% of patients and was not correlated with GC doses and treatment duration. Z-score BMI was positively correlated with blood pressure, triglycerides, LDL-c levels, and HOMA-IR. NR3C1 polymorphisms, BclI and A3669G, were found in 23.1% and 9.7% of alleles, respectively. A3669G carriers presented higher LDL-c levels compared to wild-type subjects. BclI-carriers and noncarriers did not differ. Conclusion. Our results suggest that A3669G-polymorphism could be involved with a susceptibility to adverse lipid profile in pediatric CAH patients. This study provides new insight into the GR screening during CAH treatment, which could help to identify the subgroup of at-risk patients who would most benefit from preventive therapeutic action.

Association study of glucocorticoid receptor genetic polymorphisms with efficacy of glucocorticoids in systemic lupus erythematosus: A prospective cohort study

The response to glucocorticoids (GCs) for patients with systemic lupus erythematosus (SLE) is characterized by wide interindividual variability, with a significant number of patients who have no response. We analyzed whether genetic polymorphisms within glucocorticoid receptor (GR) gene are related to variability in the efficacy of GCs in Chinese population with SLE. A cohort of 220 patients with SLE was studied. These patients were treated with GCs (prednisone) for 12 weeks. The efficacy of GCs was measured with the scores on SLE disease activity index (SLEDAI). Patients were classified into two groups (sensitive and insensitive) according to their response to GCs. Polymorphisms of GR gene were genotyped by using multiplex SNaPshot method. A total of 212 patients (96.4%) were included in the final data analyses. Of these patients, 110 patients were considered sensitive to GCs, and 102 patients were considered insensitive to GCs. Eighteen tag single nucleotide polymorphisms (SNPs) of GR gene were selected. Significant associations were seen for rs4912905 (dominant model: crude OR = 0.410, 95%CI = 0.233–0.722, p = 0.002; adjusted OR = 0.419, 95%CI = 0.233–0.754, p = 0.004), rs17100234 (dominant model: crude OR = 0.521, 95%CI = 0.282–0.963, p = 0.038; adjusted OR = 0.520, 95%CI = 0.279–0.970, p = 0.040) and rs7701443 (recessive model: crude OR = 2.736, 95%CI = 1.183–6.331, p = 0.019; adjusted OR = 2.639, 95%CI = 1.116–6.239, p = 0.027) in GR gene, but not for other polymorphisms (p > 0.05). The results of the present study suggest that GR genetic polymorphisms may play a major role in the efficacy of GCs in Chinese population with SLE.

The therapeutic outcome of intravenous steroid therapy for active Graves' orbitopathy is influenced by the time of response but not polymorphisms of the glucocorticoid receptor

Glucocorticoids are the mainstay of immunosuppression for active moderate-severe Graves' orbitopathy (GO). To analyze the response to therapy and the contribution of glucocorticoid receptor (GR) gene polymorphisms to the therapeutic outcome of intravenous glucocorticoids (IVGC) in active moderate-severe GO. we have studied 58 patients treated with 7.5 g i.v. methylprednisolone (cumulative dose). ophthalmological assessment was performed at baseline and at 6-8, 12-16, and 24-30 weeks after the first infusion. Three GR gene polymorphisms, ER22/23EK, N363S, and BCL1, which have been associated to variable sensitivity to steroids, were studied in 43/58 patients. The therapeutic outcomes defined as: i) reduction of the clinical activity score (CAS) ≥2 points or ii) reduction of proptosis ≥2 mm or iii) improvement of diplopia according to the Gorman score were also studied in relation to treatment schedule, age, gender, duration of thyroid or GO, smoking habits, and serum TSH-receptor autoantibodies levels. In total, 70% of patients responded and had GO inactivation (CAS <4) as early as 6-8 weeks. At 12-16 weeks, the proportion of patients who became inactive increased by another 10% up to a total of 80%. ER22/23EK and N363S polymorphisms were present only in about 7%, while the Bcl1 variant was present in 30% of patients; no significant association of any of the GR polymorphisms with either the therapeutic response or the occurrence of side effects was observed. Most patients with active GO respond to IVGC as early as 6-8 weeks of therapy and the analyzed GR polymorphisms do not influence the therapeutic effect of steroids. Questions arise about the need of continuing therapy up to 12 weeks in nonresponders. We suggest that these patients may be switched to other treatments alone or in combination with steroids.

Interaction between Occupational Stress and GR Gene Polymorphisms on Essential Hypertension among Railway Workers

The aim of this study was to explore the interactions of occupational stress and glucocorticoid receptor gene (GR) polymorphisms on essential hypertension (EH) among Chinese railway workers. A case-control study was conducted with 196 EH cases and matched controls from male railway employees. Occupational stress was scaled by a validated Chinese version of the Occupational Stress Inventory. Information on risk factors for hypertension, including smoking, alcohol consumption, family hypertension history and body mass index, was collected by face to face interviews. Genotypes of GR BCL1 and G678S genes were determined with PCR-RFLP. Conditional logistic regression was applied to examine the interactions of occupational stress and GR gene polymorphisms with adjustment for potential confounders. A positive relationship was observed in the CG/GG genotype compared with the CC genotype in the GRBCL1 gene. The interaction between the GRBCL1 gene and occupational stress was statistically significant on EH. The odds ratio (OR) was 1.56 (95% CI: 0.93, 2.63) when comparing the CG/GG genotype of the GRBCL1 gene with low/medium personal strain with the CC genotype with low/medium strain, whereas the OR was 3.43 (95% CI: 1.45, 8.12) when comparing the same genotype with high strain with the same reference. A similar pattern of association was observed for the CG/GG genotype of the GRBCL1 gene with low/medium occupational stress (OR=1.32, 95% CI: 0.76, 2.30) and with high occupational stress (OR=3.58, 95% CI: 1.60, 8.02). This study suggests that the CG/GG genotype in GRBCL1 possibly interacts with occupational stress in increasing the risk for essential hypertension in the railway workers, but more studies with larger samples are needed to confirm the finding.

BclI polymorphism of the glucocorticoid receptor gene is associated with increased bone resorption in patients on glucocorticoid replacement therapy

Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive weight-adapted standard glucocorticoid replacement therapy. Clinically, some patients appear more sensitive to therapeutic administration of glucocorticoids than others. Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR) and might influence bone mineral density (BMD). To determine if bone turnover markers and BMD are associated with the GR gene polymorphism BclI in patients with PAI and CAH. A prospective, cross-sectional study including 74 PAI and 38 CAH patients. BMD was evaluated by DXA. Serum levels of bone turnover markers, minerals, vitamins and hormones, and urinary crosslinks were measured. Patients carrying the homozygous BclI polymorphism (GG) had significantly higher serum β-CrossLaps (0.37 ± 0.34 μg/l; P < 0.05) and urinary collagen crosslinks (NTX, 68.1 ± 32.4 nmol/g; P < 0.005) despite receiving the lowest average daily hydrocortisone dose of 9.9 ± 3.7 mg/m(2) (P < 0.05). The GG genotype occurred significantly more frequently in patients with increased NTX (OR=6.7, 95% CI = 1.78-25.38) than in patients with normal NTX. However, BMD was not significantly different between different allelic variants. No significant differences in associations of the genotypes with outcomes (or in clinical characteristics) were found between the sexes. Although the sample sizes were relatively small and the results should be interpreted with caution, this study suggests that the homozygous (GG) genotype may be associated with higher bone resorption in adult PAI and CAH patients. GG-carriers needed a lower hydrocortisone dose on average supporting the concept that this GR variant is associated with increased cortisol sensitivity.

The glucocorticoid receptor gene polymorphism N363S predisposes to more severe toxic side effects during pediatric acute lymphoblastic leukemia (ALL) therapy

The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele-specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non-carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities. All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse 5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies.

Associations Between Polymorphisms in the Glucocorticoid-Receptor Gene and Cardiovascular Risk Factors in a Chinese Population

BackgroundGlucocorticoid is an important regulator of energy homeostasis. Glucocorticoid receptor (GR) gene polymorphisms that contribute to variability in glucocorticoid sensitivity have been identified. We explored the associations of single-nucleotide polymorphisms (SNPs) of the GR gene with traditional cardiovascular risk factors in the Chinese Han population.MethodsWe recruited 762 consecutive adults who underwent a regular physical examination at Beijing Xuanwu Hospital. Blood pressure, glucose, lipid levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein [LDL] cholesterol and triglycerides), body mass index (BMI), and waist-to-hip ratio were measured. Fourteen tag SNPs and 5 functional SNPs were selected and genotyped using the high-throughput Sequenom genotyping platform. Differences between genotypes/alleles for each SNP were adjusted for sex and age and tested using a general linear model procedure. Various models of inheritance, including additive, dominant, and recessive, were tested.ResultsAmong the 19 SNPs examined, 5 markers were associated with cardiovascular risk factors. The rs41423247 GG genotype and the rs7701443 AA genotype were associated with higher BMI and systolic blood pressure (P < 0.0004), and the rs17209251 GG genotype was associated with higher systolic blood pressure (P < 0.0004). Lower systolic blood pressure, total cholesterol, and LDL cholesterol were observed among rs10052957 A allele carriers (P < 0.0004), and lower plasma glucose and LDL-cholesterol concentrations were observed among rs2963156 TT carriers (P < 0.0004).ConclusionsPolymorphism of the GR gene was associated with cardiovascular risk factors and may contribute to susceptibility to cardiovascular disease.

Effect of glucocorticoid receptor gene polymorphisms on asthma phenotypes

The clinical presentation of asthma results from complex gene-gene and gene-environment interactions. The natural variability of the DNA sequence within the NR3C1 gene affects the activity of glucocorticoid receptors (GCRs). The NR3C1 gene is localized on chromosome 5q31–q32. The gene coding for the GCR comprises nine exons. The structural domains of the GCR determine the biological functions of the functional domains. The observed resistance to glucocorticosteroids and the normal metabolic profile of Tth111I single nucleotide polymorphism (SNP) carriers is due to the ER22/23EK polymorphism that is present in them. BclI polymorphism significantly affects the process of alternative NR3C1 gene splicing and within that mechanism increases the sensitivity to glucocorticoids (GCs). A total of 451 subjects were enrolled in the present study, including 235 qualified to the group of bronchial asthma patients. A group of 216 healthy participants with no history of asthma or atopic conditions was qualified for the study. Genotyping was accomplished using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR-high resolution melting (HRM) methods. No statistically significant differences were observed in the frequency of Tth111I, BclI and ER22/23EK polymorphisms of the NR3C1 gene when comparing mild, moderate and severe asthma vs. the control group. Investigative analyses demonstrated statistically significant correlations for alleles and genotypes of Tth111I polymorphism of the NR3C1 gene between healthy subjects and patients with severe asthma characterized by a control profile corresponding to an Asthma Control Test (ACT)™ score ≥20. It was established that only the Tth111I polymorphism of the NR3C1 gene plays an important role in the pathogenesis of chronic bronchitis leading to the development of asthma with both allergic and non-allergic etiology.

BClI polymorphism of the glucocorticoid receptor gene is associated with increased obesity, impaired glucose metabolism and dyslipidaemia in patients with Addison's disease

Although glucocorticoids are essential for health, several studies have shown that glucocorticoids replacement in Addison's disease might be involved in anthropometric and metabolic impairment, with increased cardiovascular risk, namely if conventional doses are used. As the effects of glucocorticoids are mediated by the glucocorticoid receptor, encoded by NR3C1 gene, different polymorphisms in the NR3C1 gene have been linked to altered glucocorticoid sensitivity in general population as well as in patients with obesity or metabolic syndrome. We investigated the impact of glucocorticoid receptor gene polymorphisms, including the BclI, N363S and ER22/23EK variants, on anthropometric parameters (BMI and waist circumference), metabolic profile (HOMA, OGTT and serum lipids) and ACTH levels in 50 patients with Addison's disease (34 women and 16 men, age 20-82 year) under glucocorticoids replacement. Neither N363S nor ER22/23EK variants were significantly associated with anthropometric, metabolic or hormonal parameters, while patients carrying the homozygous BclI polymorphism GG (n = 4) showed higher (P < 0·05) BMI, waist circumference, HOMA and 2-h glucose levels after OGTT, as well as total cholesterol and triglycerides than those with wild-type genotype CC (n = 28) or heterozygous CG (n = 18). The totality of GG patients was connoted by abdominal adiposity, impaired glucose tolerance/diabetes mellitus or dyslipidaemia, while a lower percentage of CC or CG patients showed some anthropometric and metabolic alterations. These results suggest that BclI polymorphism may influence the sensitivity to glucocorticoids in patients with Addison's disease and may contribute, along with other factors, to the increase in central adiposity, impaired glucose metabolism and dyslipidaemia.

Impact of Glucocorticoid Receptor Gene Polymorphisms on the Metabolic Profile of Adult Patients with the Classical Form of 21-Hydroxylase Deficiency

BackgroundCAH patients have an increased risk of cardiovascular disease, and it remains unknown if lifelong glucocorticoid (GC) treatment is a contributing factor. In the general population, glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of CAH patients.MethodologySixty-eight adult patients (34SV/34SW) with a mean age of 28.4±9 years received dexamethasone (mean 0.27±0.11 mg/day) to obtain normal androgen levels. SW patients also received fludrocortisone (50 µg/day). Metabolic syndrome (MetS) was defined by the NCEP ATPIII criteria and obesity by BMI ≥30 kg/m2. NR3C1 alleles were genotyped, and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis.ResultsObesity and MetS were observed in 23.5% and 7.3% of patients, respectively, and were not correlated with GC doses and treatment duration. BMI was positively correlated with blood pressure (BP), triglycerides (TG), LDL-c levels and HOMA-IR and inversely correlated with HDL-c levels. BclI and A3669G variants were found in 26.4% and 9.6% of alleles, respectively. Heterozygotes for the BclI polymorphism presented with higher BMI (29 kg/m2±5.3 vs. 26 kg/m2±5.3, respectively) and waist circumference (89 cm±12.7 vs. 81 cm±13, respectively) compared to wild-type subjects. Hypertension was found in 12% of patients and heterozygotes for the BclI polymorphism presented higher systolic BP than wild type subjects. Low HDL-c and high TG levels were identified in 30% and 10% of patients, respectively, and were not associated with the NR3C1 polymorphisms. A3669G carriers and non-carriers did not differ.ConclusionIn addition to GC therapy, the BclI GR variant might play an important role in obesity susceptibility in CAH patients. Genotyping of GR polymorphisms could result in the identification of a subgroup at risk patients, allowing for the establishment of personalized treatment and the avoidance of long-term adverse consequences.