Glucocorticoid Receptor Gene Polymorphisms Research Articles

Are weight loss and metabolic outcomes of bariatric surgery influenced by candidate glucocorticoid receptor gene polymorphisms? A prospective study

ABSTRACT Background Bariatric surgery is the most effective treatment for severe obesity. There can be variation in the degree of weight reduction following bariatric surgery. It is unknown whether single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor locus (GRL) affect postoperative weight loss and metabolic outcomes. Materials/methods We studied the association between selected candidate SNPs and postoperative weight loss and metabolic outcomes in patients with severe obesity undergoing bariatric surgery. The polymorphisms rs41423247 (Bcl1), rs56149945 (N363S) and rs6189/rs6190 (ER22/23EK) were analysed. Results The 139 participants included 95 women (68.3%) and had a median (interquartile range) age of 53.0 (46.0–60.0) years and mean (SD) weight of 140.8 (28.8) kg and body mass index of 50.3 (8.6) kg/m2. At baseline, 59 patients had type 2 diabetes (T2D), 60 had hypertension and 35 had obstructive sleep apnoea syndrome treated with continuous positive airway pressure (CPAP). 84 patients (60.4%) underwent gastric bypass and 55 (39.6%) underwent sleeve gastrectomy. There were no significant differences in weight loss, glycated haemoglobin (HbA1c) or lipid profile categorized by genotype status, sex or median age. There was significant weight reduction after bariatric surgery with a postoperative BMI of 34.1 (6.8) kg/m2 at 24 months (p < 0.001). Conclusion While GRL polymorphisms with a known deleterious effect on adipose tissue mass and function may have a small, additive effect on the prevalence of obesity and related metabolic disorders in the population, we suggest that the relatively weak biological influence of these SNPs is readily overcome by bariatric surgery.

The relationship of the methylation status and polymorphism of glucocorticoid receptor gene (NR3C1) with attempted suicide or non-suicidal self-injury patients in schizophrenia.

We aim to investigate the methylation of NR3C1 gene promotor and NR3C1 BclI polymorphism in schizophrenia (SCZ) patients with attempted suicide or non-suicidal self-injury (NSSI). A sample of 112 patients with SCZ was included in the study. Structured Clinical Interview for Diagnostic and Statistical Manual-Fourth Edition Axis I Disorders was used to confirm the diagnosis according to The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria. The patients were evaluated by data forms that had sociodemographic, suicidal behavior, and NSSI information. Methylation-specific polymerase chain reaction (PCR) was used to identify the methylation of the NR3C1 gene. The analysis of the BclI polymorphism of the NR3C1 gene was evaluated by using the PCR restriction fragment length polymorphism. Our results revealed that although the NR3C1 gene methylation was not statistically significantly different, there was a significant difference in NR3C1 genotype distribution among the SCZ groups with and without attempted suicide. SCZ patients carrying the CC genotype had a lower risk of attempted suicide (Odds Ratio [OR]: 0.421; 95% Confidence Interval [CI]: 0.183-0.970; p = 0.040), while having the GG genotype in SCZ patients was associated with a higher risk of attempted suicide (OR: 3.785; 95% Cl: 1.107-12.945; p = 0.042). Additionally, due to NSSI in SCZ patients, there were no significant differences in NR3C1 gene methylation and NR3C1 genotype distribution among the groups. We propose that the NR3C1 BclI polymorphism may be associated with attempted suicide in Turkish patients diagnosed with SCZ.

Association of &lt;i&gt;NR3C1 Bcl1&lt;/i&gt; gene polymorphism with impaired programmed cell death of lymphocytes in patients with atopic bronchial asthma

Atopic asthma is a chronic disease characterized by airway obstruction, bronchial hyperresponsiveness, and inflammation. Patients show increased activation of immune cells in the airways, especially T-lymphocytes, leading to chronic inflammation. The lymphocytes of asthma patients are known to have an impairment of the type 1 and 2 programmed cell death, i.e., apoptosis and autophagy, thus contributing to prolongation and intensification of inflammatory process. As compared to apoptosis, autophagy may also contribute to cell survival under stress conditions. Its disruption and hyperactivation leads to exacerbation of allergic responses. Glucocorticoids are the main drugs for the treatment of atopic bronchial asthma by activating the glucocorticoid receptor, thus triggering anti-inflammatory response and apoptosis of the cells. However, some patients exhibit resistance to therapy due to various factors, including single nucleotide polymorphisms of NR3C1 glucocorticoid receptor gene. The highest association between asthma severity and resistance to therapy was found for the GG variant of the NR3C1 Bcl1 polymorphism. Common molecular pathways for glucocorticoid receptor activation and programmed cell death and mediating molecules suggest a significant role for the polymorphic receptor variant in cell death. The aim of our study was to evaluate the effect of a single nucleotide polymorphism (G allele, i.e., Bcl1 polymorphism of NR3C1 gene) of glucocorticoid receptor on expression levels of genes that regulate apoptosis (BCL2, CASP3) and autophagy (BECN1, LC3) in lymphocytes of patients with moderate and severe atopic bronchial asthma. The study was performed with peripheral blood samples of 24 patients aged 20 to 45 years with an established diagnosis of moderate to severe atopic bronchial asthma. Using PCR technique with restriction fragment length polymorphism (RFLP) assay, the patients were distributed according to the genotypes of the BclI polymorphism of the NR3C1 gene: 12 patients with CC genotype, 8 persons with GC genotype, and 4 cases with GG genotype. The lymphocytes were isolated in Ficoll density gradient and cultivated with dexamethasone under the conditions of nutrient depletion. The level of gene expression was determined by real-time PCR. When studying associations between various genotypes of Bcl1 polymorphism and expression of cell death marker genes, the anti-apoptotic reactions were detected in lymphocytes of patients with GG polymorphism under the influence of dexamethasone thus being a potential mechanism for development of resistance to glucocorticosteroid therapy in asthma. Impaired activation of BECN1 gene expression in patients with the GG genotype may suggest deregulation of the autophagy in this group of patients, as a mode of programmed cell death. Moreover, in patients with GC genotype during long-term cultivation, exposure to dexamethasone increases the expression of the LC3 gene, indicating a more pronounced activation of autophagy. Hence, this work demonstrates differences in response of lymphocytes to synthetic glucocorticoid therapy, and probable effect of G allele (Bcl1 polymorphism) on dysregulation of programmed cell death under the influence of dexamethasone.

Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome: Insights from the Mennonite Population.

The regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with polymorphisms and the methylation degree of the glucocorticoid receptor gene (NR3C1) and is potentially involved in the development of metabolic syndrome (MetS). In order to evaluate the association between MetS with the polymorphisms, methylation, and gene expression of the NR3C1 in the genetically isolated Brazilian Mennonite population, we genotyped 20 NR3C1 polymorphisms in 74 affected (MetS) and 138 unaffected individuals without affected first-degree relatives (Co), using exome sequencing, as well as five variants from non-exonic regions, in 70 MetS and 166 Co, using mass spectrometry. The methylation levels of 11 1F CpG sites were quantified using pyrosequencing (66 MetS and 141 Co), and the NR3C1 expression was evaluated via RT-qPCR (14 MetS and 25 Co). Age, physical activity, and family environment during childhood were associated with MetS. Susceptibility to MetS, independent of these factors, was associated with homozygosity for rs10482605*C (OR = 4.74, pcorr = 0.024) and the haplotype containing TTCGTTGATT (rs3806855*T_ rs3806854*T_rs10482605*C_rs10482614*G_rs6188*T_rs258813*T_rs33944801*G_rs34176759*A_rs17209258*T_rs6196*T, OR = 4.74, pcorr = 0.048), as well as for the CCT haplotype (rs41423247*C_ rs6877893*C_rs258763*T), OR = 6.02, pcorr = 0.030), but not to the differences in methylation or gene expression. Thus, NR3C1 polymorphisms seem to modulate the susceptibility to MetS in Mennonites, independently of lifestyle and early childhood events, and their role seems to be unrelated to DNA methylation and gene expression.

Investigation of single-nucleotide polymorphisms in the NR3C1a glucocorticoid receptor gene in Cocker Spaniels with primary immune thrombocytopenia.

BackgroundIn dogs, 6 single‐nucleotide polymorphisms (SNPs) have been described in the glucocorticoid receptor gene NR3C1a, 2 of which were nonsynonymous SNPs in exons 2 and 8. The clinical importance of these SNPs is unknown.ObjectivesTo investigate whether SNPs in NR3C1a are associated with clinical outcome in Cocker Spaniels with primary immune thrombocytopenia (pITP).AnimalsTwenty‐four Cocker Spaniels with pITP presented to a referral center. Dogs were classified as slow (n = 11) or fast responders (n = 12) based on time required after initiating glucocorticoid treatment to achieve a platelet count >70 000/μL.MethodsDeoxyribonucleic acid was extracted from stored blood samples before amplification by PCR and sequencing of exons 2 and 8 of NR3C1a. Associations between genotype and clinical response variables were investigated.ResultsNeither previously identified nonsynonymous SNPs were identified. The synonymous SNP NR3C1a:c.798C>T in exon 2 was found at an increased prevalence compared to a previous report. No difference was found in prevalence of any genotype at NR3C1a:c.798C>T between fast and slow responders (P = .70).Conclusions and Clinical ImportanceNone of the previously reported nonsynonymous SNPs in exons 2 and 8 of the NR3C1a gene were detected in our cohort of Cocker Spaniels with pITP. The synonymous SNP NR3C1a:c.798C>T in exon 2 was reported at a higher frequency than previously, but was not associated with outcome measures that estimated responsiveness to glucocorticoids.

Apilot study Impact of glucocorticoid receptor gene polymorphism on the metabolic profile of child patients with classical form of 21-hydroxylase deficiency

Apilot study Impact of glucocorticoid receptor gene polymorphism on the metabolic profile of child patients with classical form of 21-hydroxylase deficiency

Association of the Glucocorticoid Receptor Gene Polymorphisms with TGF-β1 mRNA Expression in Childhood Asthma

Background: Glucocorticoid (GC) is a fundamental drug used to treat asthma. GC binds to its corresponding receptor (GR) to formulate a complex that increases the production of anti-inflammatory factors and decreases the amount of pro-inflammatory mediators, covering many cytokines. GR is a nuclear receptor superfamily protein, encoded by NR3C1 gene. Studies suggest that polymorphisms of the NR3C1 gene contribute to a decreased response to GC for the treatment of asthma, even leading to drug-resistance. Also, TGF-β1 plays a central role in airway remodeling, GC significantly inhibits the production of TGF-β1, and TGF-β1 can induce GC resistance. Thus, it is possible that the polymorphisms of the NR3C1 gene can affect the expression of TGF-β1 mRNA and tissue remodeling. Objectives: This study evaluates the effect of polymorphisms (TthIII1, BclI, ER22/23EK, and N363S) of the NR3C1 GR gene on TGF-β1 mRNA expression in children with asthma. Methods: The samples of this study included 52 outpatients (age range: 6 - 14 years) with asthma referred to Huai’an First People’s Hospital, Nanjing Medical University, from January 2018 to June 2019. Meanwhile, 40 healthy volunteers were included as the control group. Results: The polymorphisms of the NR3C1 GR gene were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and TGF-β1 mRNA levels were measured by real-time reverse transcription (RT)-PCR. TthIII1 and TGF-β1 mRNA expression levels had significant (P = 0.011) correlations. But BclI showed no e effect on TGF-β 1 mRNA, N363S, and ER22/23EK had not been examined. Conclusions: According to the results, there was a relationship between single nucleotide polymorphisms (SNPs) of the NR3C1 gene and TGF-β1 mRNA in asthmatic children. TthIII1 CC and CT genotype have the strongest induction effect on the expression of TGF-1. The phenomenon suggests that SNPs may be involved in the asthma pathology.

Analysis of glucocorticoid receptor gene polymorphisms in kidney recipients with post-transplant diabetes

Introduction: Post-transplant diabetes mellitus (PTDM) is a severe and common metabolic problem after transplantation. Glucocorticoid receptor (GR) is encoded by the NR3C1 gene and it seems that polymorphisms in this gene lead to altering insulin sensitivity. Objectives: This study aimed to evaluate the frequency of four common polymorphisms in the NR3C1 gene of renal recipients with and without PTDM. Patients and Methods: Blood samples were collected from 32 PTDM and 59 non-diabetic renal-transplanted patients. After DNA extraction, DNA fragments were amplified and directly sequenced using specific primers. Data analysis was performed with SPSS 22.0 software. Results: There was no significant correlation between diabetes incidence and the four investigated polymorphisms of the GR gene. Nevertheless, diabetic patients’ age was higher than non-diabetic patients. Additionally, transplant acute rejection (AR) in diabetic patients was found to be more than non-diabetic patients. Conclusion: Based on gathered information in this research, none of the studied polymorphisms affected the development of PTDM. Further investigations should be conducted in a large sample size.

The association between glucocorticoid receptor (NR3C1) gene polymorphism and difficult-to-treat rhinosinusitis.

Difficult-to-treat rhinosinusitis (DTRS) seriously affects the quality of work and life of patients, and the cause is still unclear. We aimed to explore the association between the glucocorticoid receptor (NR3C1) gene polymorphisms and DTRS. A nested case-control study was conducted. The exons of NR3C1 gene were sequenced by an ABI 9700 DNA analyzer in 30 DTRS patients and 70 matched chronic rhinosinusitis (CRS) patient with good outcome (non-DTRS). The genotypic and allele frequencies were calculated and linkage disequilibrium was analyzed. The three SNPs showed a significant difference between the DTRS and non-DTRS groups. In allelic model analysis, we found that the allele "C" of rs6196, the allele "A" of rs258751, and the allele "T" of rs6194 were associated with increased the risk of DTRS (all p < 0.05). In addition, the haplotype CAT of the 3 SNPs was detected to be significantly associated with DTRS risk (p = 0.001), while the haplotype TGC was associated with the decreased risk of DTRS (p = 0.008). NR3C1 gene polymorphisms are significantly associated with the DTRS.

NR3C1 Glucocorticoid Receptor Gene Polymorphisms Are Associated with Membranous and IgA Nephropathies.

Glomerular diseases (GNs) are responsible for approximately 20% of chronic kidney diseases. Glucocorticoid receptor gene (NR3C1) single nucleotide polymorphisms (SNPs) are implicated in differences in predisposition to autoimmunity and steroid sensitivity. The aim of this study was to evaluate the frequency of the NR3C1 SNPs—rs6198, rs41423247 and rs17209237—in 72 IgA nephropathy (IgAN) and 38 membranous nephropathy (MN) patients compared to 175 healthy controls and to correlate the effectiveness of treatment in IgAN and MN groups defined as a reduction of proteinuria <1 g/24 h after 12 months of treatment. Real-time polymerase chain reactions and SNP array-based typing were used. We found significant rs41423247 association with MN (p = 0.026); a significant association of rs17209237 with eGFR reduction after follow-up period in all patients with GNs (p = 0.021) and with the degree of proteinuria after 1 year of therapy in all patients with a glomerulopathy (p = 0.013) and IgAN (p = 0.021); and in the same groups treated with steroids (p = 0.021; p = 0.012). We also observed the association between rs41423247 and IgAN histopathologic findings (p = 0.012). In conclusion, our results indicate that NR3C1 polymorphisms may influence treatment susceptibility and clinical outcome in IgAN and MN.

Association of Stress, Glucocorticoid Receptor, and FK506 Binding Protein Gene Polymorphisms With Internalizing Disorders Among HIV-Infected Children and Adolescents From Kampala and Masaka Districts-Uganda.

Children and adolescents living with human immunodeficiency virus (CA-HIV) suffer a considerable burden of internalizing disorders (IDs; depressive and anxiety disorders). Environmental and genetic factors have been reported to influence the vulnerability to IDs in western settings; however, their role among African populations remains inadequately explored. We investigated the individual and interactive effects of stress and single-nucleotide polymorphisms within the FK506 binding protein 5 (rs1360780) and glucocorticoid receptor (rs10482605) genes on ID status in a cohort of CA-HIV in Uganda. We genotyped rs10482605 (309 cases and 315 controls) and rs1360780 (350 cases and 335 controls) among CA-HIV with and without IDs using Kompetitive Allele-Specific PCR. Socio-demographic variables, as well as allele and genotype distributions, were compared between cases and controls using chi-square tests. Genotypes were assessed for Hardy–Weinberg equilibrium. Composite indices of recent and chronic stress classes were also generated. A hierarchical cluster analysis was used to generate cutoff points within each of the indices of recent and chronic stress. Logistic regression was used to assess the association between IDs and each of recent stress, chronic stress, and the investigated genotypes. The interaction effect of chronic/recent stress on the association between each of the polymorphisms and IDs was determined using a likelihood ratio test. We observed no significant association between IDs and rs1360780 and rs10482605 polymorphisms within the FKBP5 and glucocorticoid receptor genes, respectively (P > 0.050). Severe recent stress increased the vulnerability to IDs among CA-HIV (P = 0.001). We did not observe any gene–environment effect on vulnerability to IDs in this population. These findings support the currently held opinion that polymorphisms at single genetic loci only contribute a very small effect to the genetic vulnerability to IDs.

Glucocorticoid receptor Gene (NR3C1) Polymorphisms and Haplotypes in patients with congenital adrenal hyperplasia

BackgroundLifelong glucocorticoid (GC) replacement is the mainstay treatment of congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency (21-OHD). Challenges posed by therapeutic management of these patients are well known, but novel insights into the variability in clinical response to GC highlight a role for single nucleotide polymorphisms (SNPs) of the glucocorticoid receptor gene (NR3C1). AimTo assess whether six commonly studied NR3C1 SNPs, which were previously associated with modified response to GC, are associated with CAH. We further assessed the linkage disequilibrium (LD) among these NR3C1 SNPs and their combination into haplotypes. MethodsGenotypes were determined by Taqman allele discrimination assays for Tth111I (rs10052957), ER22 (rs6189), 23 EK (rs6190), N363S (rs56149945), BclI (rs41423247) and 9β (rs6198) in a Brazilian cohort of 102 unrelated 21-OHD patients and 163 unrelated healthy subjects (controls). Haplotypes were estimated using Haplo.stats, and LD among SNPs using Haploview. ResultsHeterozygous subjects for Tth111I were more frequent in 21-OHD patients (P = 0.004), while heterozygous for BclI were more frequent in controls (P = 0.049). We found a strong LD among the six NR3C1 SNPs, and four out of six common haplotypes contained the Tth111I-variant. Although we found no significant differences in overall haplotype analysis, the BclI-haplotype was less frequent among 21-OHD patients (P = 0.0180). ConclusionsBclI-haplotype was less common and heterozygous for Tth111I were more frequent in 21-OHD patients, while heterozygous for BclI were more frequent in controls. Our novel findings may contribute to further clinical studies on the prognostic value of NR3C1 haplotypes towards individualized treatment for 21-OHD patients.

Association of glucocorticoid receptor gene polymorphism A3669G (9β) with lower glucose concentration 2 hours after OGTT in patients during chronic glucocorticoid treatment

Association of glucocorticoid receptor gene polymorphism A3669G (9β) with lower glucose concentration 2 hours after OGTT in patients during chronic glucocorticoid treatment

Relationship between postmenopausal osteoporosis and glucocorticoid receptor gene (NR3C1) polymorphism in a Turkish population

IntroductionGlucocorticoids (GCs) are used in the treatment of numerous diseases, and long-term use of GCs causes bone loss. GC receptor activation decreases Bone Mineral Density (BMD) by inhibiting and stimulating osteoblasts and osteoclasts, respectively. GC receptor gene polymorphisms are also associated with increased susceptibility to GCs. The purpose of this study was to assess the relationship between osteoporosis and Glucocorticoid receptor gene (NR3C1) polymorphism in Turkish population.Material and methodsThe study group consisted of 232 unrelated patients with osteoporosis and 150 unrelated healthy controls. All participants, patients and healthy controls, were of Turkish origin, from the central region of Turkey. Genomic DNA was isolated from whole venous blood samples using a commercial DNA isolation kit. The NR3C1 BclI gene C/G polymorphism was analyzed by polymerase chain reaction.ResultsThe frequencies of CC, CG and GG genotypes in the patients were 34.5%, 48.3%, and 17.2% and in the controls were 48.0%, 42.0%, and 10.0%. A statistically significant difference was observed between patients and controls according to genotype frequencies (p=0.01). C and G allele frequencies of C/G polymorphism were 58.6% and 41.4% in patient group and 69.0% and 31.0% in control group (p=0.005).ConclusionsThe NR3C1 BclI gene C/G polymorphism could be one of the genetic factors causing osteoporosis.

Associations of Chinese social face with cortisol level and glucocorticoid receptor gene

A major source of social stress in the Chinese society is losing face. Inspired by the roles of cortisol functions in stress-coping, we investigated whether cortisol functions (e.g., cortisol level and glucocorticoid receptor gene) are related to social face in Chinese. Study 1 examined the association between salivary cortisol level and social face among 134 college students; and Study 2 investigated associations between the polymorphisms (i.e., rs41423247 and rs10052957) of glucocorticoid receptor gene (NR3C1) and social face among 688 college students. Results from Study 1 indicated that salivary cortisol level was positively correlated to the scores on social face; and results from Study 2 showed that the GG genotype of rs41423247, which is related to higher receptor expression, was related to higher social face score as compared with the C allele. Moreover, the association between rs41423247 and social face was mediated by public self-consciousness. These findings highlight the importance of cortisol functions to social face and demonstrate a link between genetic polymorphism, social face and public self-consciousness.

Clinicopathological Impact of Gene Polymorphism of Nephrin and Glucocorticoid Receptor Genes in Egyptian Children with Nonfamilial Nephrotic Syndrome.

Idiopathic nephrotic syndrome (NS) is one of the most common primary glomerular diseases in children. In this study, we investigate the association of single-nucleotide polymorphisms of nephrin gene and glucocorticoid receptor gene (NR3C1) and susceptibility to develop NS and the response to steroid therapy in 100 Egyptian children with NS using polymerase chain reaction-restriction fragment length polymorphism. We also analyzed the correlation between the genotypes and clinicopathologic features of the patients. Thirty-four patients (34%) were initial steroid nonresponders, renal biopsy findings of those patients were available, of which 22 (64.7%) showed minimal change NS and 12 (35.3%) had focal segmental glomerulosclerosis. The distribution of the genotypes was comparable between the patient and control groups, allele frequencies showed no significant difference between the patient's group and the control group. The genotypes showed no correlation with the age of onset of NS, initial steroid responsiveness, renal pathologic findings, estimated glomerular filtration rate (eGFR), and serum albumin. However, 24-h protein in urine showed a significant association with the NR3C1 gene. These data suggested that the nephrin gene and NR3C1 gene SNPs do not affect the development of NS, initial steroid responsiveness, renal pathological lesion, eGFR, and serum albumin. However, 24-h protein in urine showed a significant association with the NR3C1 gene in Egyptian children with NS.

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).

SAT-310 Analysis of the Influence of Glucocorticoid Receptor Gene Polymorphism BCL-1 on Clinical and Psychiatric Manifestations in Brazilian Patients with Cushing’s Disease

In Cushing’s disease (CD), the spectrum of clinical manifestations is considerably wide, and the intensity of symptoms does not correlate with the magnitude of cortisol hypersecretion or with pituitary tumor size. Polymorphisms in the gene that encodes the glucocorticoid receptor (GR), an essential regulator of the hypothalamic-pituitary-adrenal axis, have been linked to some psychiatric disorders. Considering that psychiatric manifestations are present in nearly all patients with hypercortisolism, we hypothesized a possible correlation of polymorphisms in the GR gene and clinical and psychiatric manifestations, in CD. To investigate the frequency and clinical implications of the GR gene polymorphism Bcl-1 in patients with CD, we conducted a cross-sectional, case-controlled study. Fifty-three Brazilian patients with CD aged between 12 and 75 years and one hundred healthy controls aged between 42 and 67 years, of both genders, who provided written informed consent, were enrolled. Blood samples were collected from patients for DNA extraction and sequencing for analysis of the GR gene polymorphism Bcl-1. Clinical data (obesity, skin lesions, muscle weakness, hypertension, diabetes, hypokalemia, and sex-related disorders) were obtained through retrospective analysis of medical records, appointment with endocrinologist and with psychiatrist. Mini International Neuropsychiatric Interview, scales self-applicable of anxiety and depression were used to address psychiatric conditions. From the 53 patients studied, 48 were women (90,56%), and 16 patients had macroadenoma (2 of them had tumors larger than 4 cm). Overall frequencies of the Minor Allele for Bcl-1 polymorphism, which corresponds to the risk allele for psychiatric illness in the normal population, did not significantly differ between CD patients (67.92%) and controls (74.00%). Similarly, differences in Minor Allele Frequencies among subgroups of patients presenting with psychiatric and clinical manifestations of CD were not statistically significant. Although data from the literature strongly suggests a correlation between Bcl-1 polymorphism with psychiatric disorders (especially depression) in the normal population, this association was not observed in our cohort of patients with CD. More studies are needed to better clarify a possible role for GR gene polymorphisms as modifiers of the spectrum of psychiatric and clinical manifestations of CD.

Impact of glucocorticoid receptor gene polymorphisms on occurrence of steroid-induced adverse events

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

Glucocorticoid receptor (NR3C1) gene polymorphisms are associated with age and blood parameters in Polish Caucasian nonagenarians and centenarians.

Polymorphism of the glucocorticoid receptor gene (NR3C1) may modify protein abundance or function and therefore disturb human homeostasis. Variant frequencies of the three NR3C1 polymorphisms, rs2963154, rs10515522 and rs2918418, selected in silico as associated with longevity, was analyzed in 552 DNA samples from 95 to 106-year-old individuals and in 284 samples of cord blood DNA from newborns. Frequencies of the TT genotypes of rs2963154 and rs10515522, and of the rs291841 CC genotype, were higher in the long-lived study subjects (p = 0.002, p = 0.016 and p = 0.028, respectively). In the long-lived cohort, the rs2963154 CC genotype was associated with higher concentrations of total (p = 0.007) and high-density cholesterol (p = 0.039). The rs10515522 CC genotype was associated with a higher concentration of total cholesterol (p = 0.049). The rs2918418 GG genotype was associated with higher concentrations of total (p = 0.03) and low-density cholesterol (p = 0.03). None of the polymorphisms was associated with fasting glucose, C-reactive protein levels and white blood count, prevalence of diabetes, stroke, myocardial infarction, or cognitive function. However, carriers of the rs10515522 minor allele had significantly better survival rates than carriers of other genotypes. NR3C1 polymorphisms modify cholesterol levels, and may affect the survival rates of individuals in their tenth and eleventh decades of life.