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.

Topical Tacrolimus in Patients with Hands Eczema Taking into Account the Severity of Dermatoses, Some Cytokine Profile Indicators, Content of Vitamin D and Genetic Polymorphism of the Glucocorticoid Receptor Gene

The purpose of the study was to evaluate and compare the therapeutic capacity of 0.1% topical tacrolimus ointment in patients with hand eczema who were resistant to glucocorticoid treatment, taking into account the severity of dermatosis, interleukin-17A and interleukin-2 concentrations, vitamin D and genetic polymorphism of the glucocorticoid receptor gene. Materials and methods. The venous blood of 143 patients with hand eczema aged (42.2±11.1) years was used in the study. During the patients examination the data on age, sex, body mass index (kg/m2), body mass index ≥25 kg/m2 (%), smoking, IgE (iu/ml), interleukin-17A (pg/ml), interleukin-2 (pg/ml), and 1,25(OH)2D3 (ng/ml) were obtained. The Hand Eczema Severity Index was also assessed in each subject. According to the Hand Eczema Severity Index value all patients were divided into three subgroups: mild, moderate and severe eczema. Patients with mild and moderate eczema were appointed topical glucocorticoid 0.1% mometasone furoate cream twice a day for 2 weeks. Patients with severe hand eczema was appointed additionally systemic corticosteroid – a solution of dexamethasone by intramuscular injection at the dose of 8 mg/day No. 3, then another 4 mg/day for other 2 days. After 2 weeks, individuals who did not respond well to glucocorticoid treatment were prescribed tacrolimus 0.1% ointment twice a day for 2 weeks. BclI SNP (rs41423247) of the glucocorticoid receptor gene (NR3C1) was determined using the polymerase chain reaction-restriction fragment length polymorphism method (Fleury et al. 2003). The statistical analysis was performed using the program SPSS 22.0. The quantitative variables were tested for normal distribution by the Shapiro-Wilk method. The comparisons of the means between the two subgroups were performed using Student's t-test for independent samples. The comparison of the frequencies distribution in the subgroups was performed using the Pearson test. The P value <0.05 was considered as significant. Results and discussion. Findings in a previous study showed that not all people with hand eczema responded well to treatment with topical 0.1% mometasone furoate cream and systemic glucocorticoid. After 2 weeks of topical tacrolimus, of 51 patients who were not responsive to glucocorticoid treatment, 39 responded well to therapy. The concentration of interleukin-17A in the blood serum of such people was significantly lower than in people who did not respond to treatment. Conclusion. We did not find any differences in the content of immunoglobulin E, interleukin-2, 1α,25(OH)2D3 and BclI polymorphism of the glucocorticoid receptor gene in the subjects under study

DNA methylation of the glucocorticoid receptor gene predicts substance use in adolescence: longitudinal data from over 1000 young individuals

Early life stress has been linked to increased methylation of the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene, which codes for the glucocorticoid receptor. Moreover, early life stress has been associated with substance use initiation at a younger age, a risk factor for developing substance use disorders. However, no studies to date have investigated whether NR3C1 methylation can predict substance use in young individuals. This study included adolescents 13–14 years of age that reported no history of substance use at baseline, (N = 1041; males = 46%). Participants contributed saliva DNA samples and were followed in middle adolescence as part of KUPOL, a prospective cohort study of 7th-grade students in Sweden. Outcome variables were self-reports of (i) recent use, (ii) lifetime use, and (iii) use duration of (a) alcohol, (b) tobacco products, (c) cannabis, or (d) any substance. Outcomes were measured annually for three consecutive years. The predictor variable was DNA methylation at the exon 1 F locus of NR3C1. Risk and rate ratios were calculated as measures of association, with or without adjustment for internalizing symptoms and parental psychiatric disorders. For a subset of individuals (N = 320), there were also morning and afternoon salivary cortisol measurements available that were analyzed in relation to NR3C1 methylation levels. Baseline NR3C1 hypermethylation associated with future self-reports of recent use and use duration of any substance, before and after adjustment for potential confounders. The overall estimates were attenuated when considering lifetime use. Sex-stratified analyses revealed the strongest association for cigarette use in males. Cortisol analyses revealed associations between NR3C1 methylation and morning cortisol levels. Findings from this study suggest that saliva NR3C1 hypermethylation can predict substance use in middle adolescence. Additional longitudinal studies are warranted to confirm these findings.

Methylation of the glucocorticoid receptor gene NR3C1: a summary for clinicians working with children and families

AimsIt has been shown that the glucocorticoid receptor NR3C1 gene can be methylated (“switched off”) in response to early adversity. Methylation has also been linked to physiological changes in the body's response to stress by changing the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. In adults, associations have been made between NR3C1 methylation and borderline personality disorder, depression and post-traumatic stress disorder. Environmental and social co-variates increase with lifespan so establishing cause and effect is difficult. Studies in children, then, may illuminate patterns to inform current hypotheses.This paper reviews the literature on children and adolescents linking glucocorticoid gene receptor NR3C1 to the psychopathology of mental illness. Findings are presented in an accessible manner to engage people less familiar with genetics and to inform frontline clinicians of this quickly growing area of research.MethodMEDLINE and PsychINFO were searched for relevant peer-reviewed original research using the following keywords and associated mesh terms: NRC31, glucocorticoid receptor gene, methylation, epigenetics, child, adolescent, trauma, psychopathology, gene expression.Result14 studies were identified involving 5475 young people. Degree of NR3C1 methylation was associated with severity of early life adversity. Methylation was linked with psychopathology including borderline personality disorder, internalising symptoms and externalising symptoms with sex differences. The most consistent association was with depression. Methylation seems to modulate the interaction between environment and genetics with the suggestion that the effect may be protective in some cases. However, longitudinal genetic sampling was only conducted in one study.ConclusionHeterogeneity of studies in the epigenetics field are discussed but should not detract from future possibilities. The hope is to identify therapeutic targets or monitor response to treatment as we work to better understand the biology of developmental psychology, mental illness and resilience. There is a growing understanding that epigenetic modifications likely change over time and clinical significance is most likely dictated by changes at multiple gene locations. Thus future research may need to move away from single gene research typically employed in favour of longitudinal whole genome studies in larger population studies.It is time that clinicians integrate the concepts of “epigenetic adaptation to environmental stress” with “nature vs. nurture” in their psychoeducation with families. To understand that one's problems might be the symptom of environmental mismatch, and potentially reversible too, can bring validation and hope to families.

Association between childhood maltreatment, psychopathology and DNA methylation of genes involved in stress regulation: Evidence from a study in Borderline Personality Disorder

Previous research suggests that childhood maltreatment is associated with epigenetic modification of genes involved in hypothalamic-pituitary-adrenal (HPA) functioning, which could cause dysregulation of the stress response system. If pervasive, this may be associated with the development of stress-related disorder in adults, including affective disorders, anxiety disorders, post-traumatic stress disorder (PTSD) or borderline-personality disorder (BPD). The majority of studies have focused on DNA methylation of the glucocorticoid receptor gene (NR3C1) and the FKBP5 encoding gene, which regulates the sensitivity of the glucocorticoid receptor (GR). How methylation of NR3C1 and FKBP5 interferes with childhood adversity and psychopathology as well as empathy is an under-researched issue. Here, we sought to investigate the association of childhood maltreatment in a sample of 89 individuals (44 healthy participants and 45 patients diagnosed with BPD) with the methylation of the 1F promoter region of NR3C1 and the intron 7 of FKBP5 as well as with different measures of psychopathology and empathy. Methylation of FKBP5 (bin 2) correlated with anxiety (SCL-90-R) and the global psychopathological symptom load index (GSI), as well as with lower empathic perspective-taking abilities. Psychopathology and empathy impairments correlated with the level of childhood maltreatment. No difference in FKBP5 methylation was observed between the clinical and the non-clinical group. Methylation of NR3C1 was lower in BPD patients compared to controls, yet with small differences. The results are discussed regarding their biological relevance, including possible evolutionary explanations. In short, the regulation of the GR sensitivity by methylation of FKBP5 correlated with psychopathology and empathy scores, while no correlation emerged with the severity of childhood adversity.