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  • Overnight mg dexamethasone suppression testing

    2022-05-19

    Overnight 1-mg dexamethasone suppression testing (DST) of the BclI polymorphism carriers found them to have lower cortisol levels, suggesting an increased sensitivity to GCs with respect to the transrepression effect of cortisol on the POMC gene of the corticotroph pituitary cells [28]. The exact mechanism through which the BclI polymorphism may alter GC effects has not been determined. The BclI polymorphism does not involve a coding, regulatory or splicing region of the GR gene. Most likely this polymorphism is linked to other functionally important polymorphisms. Genotype analysis for the rs2918419 and BclI GR polymorphisms in Caucasian men performed by Syed et al. found no significant differences in wild-type BclI (G/G) vs. variant (G/C or C/C) genotype frequencies between subjects categorized by presence or absence of the metabolic syndrome or components of it. [29] In contrast, men who were homozygous or heterozygous for the rs2918419 GR polymorphism had a higher prevalence of insulin resistance and higher mean fasting insulin concentration compared to the wild type carriers. Such association, however, was not found in women, suggesting an integral role of sex hormones in the clinical implications of that GR polymorphism. Interestingly, analysis of the combined effect of rs2918419 and BclI polymorphisms showed that men with BclI variant Ginsenoside Rb1 sale on a background of rs2918419 wild-type alleles had the lowest fasting insulin concentrations. Thus, carrying Bcl1 variant alleles alone without rs2918419 variant alleles was not associated with elevated fasting insulin concentrations. The presence of the rs2918419 variant was necessary for the association of those two intron 2 GR polymorphisms with insulin resistance. No conclusions of the rs2918419 alone on insulin resistance can be extracted from the current study since all subjects with the rs2918419 variants were carriers of the BclI variants, supporting the possibility of a locus in linkage disequilibrium with the BclI restriction site contributing to insulin resistance. With changes in cortisol levels, recent studies support the associations of BclI polymorphism with alterations of the HPA axis rather than altered anthropometric measurements, metabolic derangements and body composition [30]. Similar HPA axis alterations in association with GR and CBG gene polymorphisms, without significant differences in adipose tissue distribution, were reported in a study of prepubertal obese children [31]. However, a trend for a higher percentage of fat mass was detected in GR G/G carriers. As supported by other studies [32], carriage of an extended intron 2 haplotype that includes the rs2918419 polymorphism downstream of the BclI site is most likely linked to hyperinsulinemia. The opposite trend was observed in homozygous carrier of the rare Tth111I allele, although the results did not reach statistical significance. Carriers of the Tth111I variant showed elevated basal cortisol secretion and bedtime levels of salivary cortisol [33]. Evidence of partial linkage to the ER22/23EK polymorphism is associated with decreased glucocorticoid sensitivity [34]. Another well studied polymorphism of the GR gene is the N363S variant, which is located in codon 363 of exon 2. It results from an AAT→AGT nucleotide change. This polymorphism results in substitution of asparagine by serine. Although in vitro testing of this GR polymorphism did not show any changes in its trans-activating capacity [35], [36], increased sensitivity to GCs was found in vivo [37]. Russcher et al. reported a significant increase in transactivation of the GC response element luciferase reporter gene by the N363S variant constructed GR [38]. However, another group failed to replicate those findings but showed that in the presence and absence of dexamethasone, the N363S variant can regulate a novel set of genes compared to the wild-type GR [39]. The overnight 1-mg DST, showed no differences between N363S carriers and controls, but there was a significantly higher insulin response in N363S carriers. Using a lower dexamethasone dosage (0.25mg) for the overnight DST, a significantly larger cortisol suppression and higher insulin response was noted in N363S carriers without differences to the number of GR or the ligand binding affinity. With respect to anthropometric measurements, a significantly higher BMI was seen in N363S carriers compared to non-carriers indicating a strong association between the N363S variant and obesity. However, larger studies have demonstrated conflicting results. A study of 491 UK Caucasian subjects found the frequency of the G allele was equal among subjects with BMI<25kg/m2 and BMI>25kg/m2 [40], suggesting that the 1220A>G GR variant is not associated with anthropometric parameters. No association of the A-to-G point variation in exon 2 of the GR gene with obesity or cardiometabolic parameters was found in 3 subsequent studies [21], [41], [42]. The association between the 1220A>G polymorphism in exon 2 and obesity was further hampered by contradictory results, although the majority of reports were negative. Subsequent studies, in which a significantly higher mean value of BMI was found in heterozygotes for the 1220A>G polymorphism, using a different statistical analysis, (2×2 tables), found that the relative risk for obesity in the 1220A>G carriers was not significantly increased [43]. This inconsistency may reflect the importance of publication bias and over-interpretation of marginal findings.