Increased Expression of the Glucocorticoid Receptor-A Translational Isoform as a Result of the ER22/23EK Polymorphism

Department of Internal Medicine, Room Ee 593, Erasmus MC, University Medical Center Rotterdam, Molewaterplein 40, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Molecular Endocrinology (Impact Factor: 4.02). 08/2005; 19(7):1687-96. DOI: 10.1210/me.2004-0467
Source: PubMed


One of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased survival rate. Recently, Yudt and Cidlowski reported that two different methionine codons in the GR mRNA may be used as initiation codon: AUG-1 and AUG-27, resulting in two isoforms, the GR-A and the GR-B proteins, respectively. They also showed that the GR-B protein had a stronger transactivating effect in transient transfection experiments. In this study, we elucidated the molecular basis for the reduced GC sensitivity by investigating the influence of the ER22/23EK polymorphism on synthesis of GR-A and GR-B by expressing them independently from constructs with and without the polymorphic site. Binding studies with [(3)H]-dexamethasone and transactivation studies showed that, when the ER22/23EK polymorphism is present, approximately 15% more GR-A protein was expressed, whereas total GR levels (GR-A + GR-B) were not affected. These results show that the transcriptional activity in GR(ER22/23EK) carriers is decreased because more of the less transcriptionally active GR-A isoform is formed. This is probably caused by altered secondary mRNA structure.

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    • "SNPs in the genes FKBP5, NR3C1, and CRHR1 have been selected for genotyping based on published positive association studies with depression or depressive symptoms for the respective SNPs and haplotypes (see Section 1). The SNPs with the strongest gene environment interaction effects, which mean depressive symptoms, were selected (CRHR1 SNPs: rs7209436 and rs110402 [28, 40]; NR3C1 SNPs: rs41423247, rs6195, and rs10482605 [42, 43]; FKBP5 SNPs: rs1360780, rs9296158, rs3800373, and rs9470080 [28, 46]). SNP IDs and their minor allele frequency (MAF) are reported in Table 1. "
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    ABSTRACT: Purpose: The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in genes of the stress hormone signaling pathway, specifically FKBP5, NR3C1, and CRHR1, are associated with depressive symptoms during and after pregnancy. Methods: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for the assessment of maternal and fetal health including the assessment of depressiveness. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of the pregnancy, visit 2 was shortly after birth, and visit 3 was 6-8 months after birth. Germline DNA was collected from 361 pregnant women. Nine SNPs in the above mentioned genes were genotyped. After construction of haplotypes for each gene, a multifactorial linear mixed model was performed to analyse the depression values over time. Results: EPDS values were within expected ranges and comparable to previously published studies. Neither did the depression scores differ for comparisons among haplotypes at fixed time points nor did the change over time differ among haplotypes for the examined genes. No haplotype showed significant associations with depressive symptoms severity during pregnancy or the postpartum period. Conclusion: The analysed candidate haplotypes in FKBP5, NR3C1, and CRHR1 did not show an association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.
    03/2014; 2014:469278. DOI:10.1155/2014/469278
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    • "The second variant results in arginine (R) to lysine(K) change. Presence of the ER22/23EK allele is related to the resistance to GC [21]. Additionally, C-reactive protein concentration [19] and changes in the balance between two isoforms of GR GRα ligand-dependent transcription factor and GRβ—having no transcriptional activity, was found to be related to the polymorphism [22, 23]. "
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    ABSTRACT: Depressive disorder is a disease characterized by disturbances in the hypothalamo-pituitary-adrenal axis. Abnormalities include the increased level of glucocorticoids (GC) and changes in sensitivity to these hormones. The changes are related to glucocorticoid receptors gene (NR3C1) variants. The NR3C1 gene is suggested to be a candidate gene affecting depressive disorder risk and management. The aim of this study was to investigate polymorphisms within the NR3C1 gene and their role in the susceptibility to recurrent depressive disorder (rDD). 181 depressive patients and 149 healthy ethnically matched controls were included in the study. Single nucleotide polymorphisms were assessed using polymerase chain reaction/restriction fragment length polymorphism method. Statistical significance between rDD patients and controls was observed for the allele and genotype frequencies at three loci: BclI, N363S, and ER22/23EK. The presence of C allele, CC, and GC genotype of BclI polymorphism, G allele and GA genotype for N363S and ER22/23EK variants respectively were associated with increased rDD risk. Two haplotypes indicated higher susceptibility for rDD, while haplotype GAG played a protective role with OR(dis) 0.29 [95 % confidence interval (CI) = 0.13-0.64]. Data generated from this study support the earlier results that genetic variants of the NR3C1 gene are associated with rDD and suggest further consideration on the possible involvement of these variants in etiology of the disease.
    Molecular Biology Reports 10/2012; 40(2). DOI:10.1007/s11033-012-2220-9 · 2.02 Impact Factor
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    • "Furthermore, the ER22/23EK polymorphism of the GR gene was found to be associated with an increased risk of S. aureus carriage. The ER22/23EK polymorphism is associated with a relative resistance for GCs for its transactivating effect, but this polymorphism may not affect the immune system since normal transinhibition of the proinflammatory nuclear factor NF-κB was observed [13]. Although numerous effects throughout the body have been reported for all these GR polymorphisms, no differences in serum cortisol levels have been described [14], suggesting that the mildly altered GC sensitivity is mostly present at the tissue level with a potential cell-specific effect. "
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    ABSTRACT: Staphylococcus aureus (S. aureus) colonizes the anterior nares in part of the population and the persistent carrier state is associated with increased infection risk. Knowledge concerning the determinants of S. aureus nasal carriage is limited. Previously, we found that glucocorticoid receptor polymorphisms influence carrier risk, suggesting involvement of glucocorticoids. Our aim was to study long-term cortisol levels in non-carriers, intermittent, and persistent carriers of S. aureus. We hypothesized that cortisol levels are higher in carriers, since cortisol-induced immune suppression would enhance S. aureus colonization. We determined nasal carrier state and long-term hair cortisol levels in 72 healthy subjects. Nasal swabs were collected twice with an interval of 2 weeks. Cortisol levels were determined in hair segments of 3 cm, which corresponds to a period of roughly 3 months. Of all 72 participants, 38 were non-carriers, 10 were intermittent carriers, and 24 were persistent carriers of S. aureus. Cortisol levels did not differ between these carrier groups (p=0.638). Long-term cortisol levels are not associated with S. aureus nasal carriage.
    European Journal of Clinical Microbiology 05/2011; 31(1):97-100. DOI:10.1007/s10096-011-1282-2 · 2.67 Impact Factor
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