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. .

Modulatory effect of BclI GR gene polymorphisms on the obesity phenotype in Brazilian patients with Cushing's disease

OBJECTIVES: Patients with Cushing's disease exhibit wide phenotypic variability in the severity of obesity, diabetes and hypertension. In the general population, several glucocorticoid receptor genes (NR3C1) and HSD11B1 polymorphisms are associated with altered glucocorticoid sensitivity and/or metabolism, resulting in an increased or reduced risk of an adverse metabolic profile. Our aim was to analyze the association of NR3C1 and HSD11B1 gene variants with the severity of some clinical and hormonal features of Cushing's disease. METHODS: Sixty-four patients presenting with Cushing's disease were diagnosed based on adrenocorticotrophic hormone levels, high-dose dexamethasone suppression tests and/or inferior petrosal sinus sampling and magnetic resonance imaging. The A3669G, ER22/23EK, N363S BclI-NR3C1 and HSD11B1-rs12086634 variants were screened. RESULTS: The BclI, HSD11B1-rs12086634 and A3669G variants were found in 36%, 19.5% and 14% of alleles, respectively. The N363S and ER22/23EK polymorphisms were identified in heterozygosis once in only two patients (1.5% of alleles). There were no differences in the weight gain or prevalence of diabetes and hypertension in the patients carrying the abovementioned alleles compared to the wild-type carriers. Interestingly, the mean body mass index (BMI) of the BclI carriers was significantly higher than the non-carriers (34.4±7 kg/m2 vs. 29.6±4.7 kg/m2, respectively). None of the polymorphisms were associated with the basal adrenocorticotrophic hormone, FU levels or F level after dexamethasone suppression testing. CONCLUSION: Although Cushing's disease results from increased glucocorticoid secretion, we observed that interindividual variability in the peripheral glucocorticoid sensitivity, mediated by the glucocorticoid receptor, could modulate the obesity phenotype. .

Frequency of genetic polymorphisms of PXR gene in the Brazilian population

INTRODUCTION: PXR polymorphisms have been implicated in modulating CYP3A4 and PXR expression, potentially accounting for interindividual differences in drug metabolism. The prevalence of PXR polymorphisms varies among ethnic groups and data on the allelic distribution in the highly mixed Brazilian population is lacking. The aim of this study was to analyze genetic variations in the PXR gene in Brazilians and to compare the results to other ethnic groups. METHODS: DNA samples from 117 healthy Brazilians underwent PCR amplification and sequencing. RESULTS: Eleven polymorphisms were identified, 3 of which are highly associated with differences in CYP3A4 expression. We also identified 1 new synonymous variant in 1.3 percent of the alleles. Among the functional polymorphisms, -25913 C>T and -6994T>C occurred at a higher frequency comparedtothe Africanalleles (p < 0.05) but at a lower frequency compared to Caucasian alleles. The 8055 C>T allele was found at a similar frequency to those described in Caucasians and Africans (p > 0.05). CONCLUSION: We observed that functional variants of the PXR were frequent in our sample of the Brazilian population. Our results suggest that PXR gene variants may be of interest in pharmacogenetic studies involving Brazilians.

Pharmacogenetics of glucocorticoid replacement could optimize the treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

INTRODUCTION: 21-hydroxylase deficiency is an autosomal recessive disorder that causes glucocorticoid deficiency and increased androgen production. Treatment is based on glucocorticoid replacement; however, interindividual variability in the glucocorticoid dose required to achieve adequate hormonal control has been observed. OBJECTIVE: The present study aimed to evaluate the association between polymorphic variants involved inglucocorticoid action and/or metabolism and the mean daily glucocorticoid dose in 21-hydroxylase deficiency patients. METHODS: We evaluated 53 patients with classical forms of 21-hydroxylase deficiency who were receiving cortisone acetate. All patients were between four and six years of age and had normal androgen levels. RESULTS: The P450 oxidoreductase A503V, HSD11B1 rs12086634, and CYP3A7*1C variants were found in 19 percent, 11.3 percent and 3.8 percent of the patients, respectively. The mean ± SD glucocorticoid dose in patients with the CYP3A7*1C and wild-type alleles was 13.9 ± 0.8 and 19.5 ± 3.2 mg/m²/d, respectively. We did not identify an association between the P450 oxidoreductase or HSD11B1 allelic variants and the mean glucocorticoid dose. CONCLUSION: Patients carrying the CYP3A7*1C variant required a significantly lower mean glucocorticoid dose. Indeed, the CYP3A7*1C allele accounted for 20 percent of the variability in the cortisone acetate dose. The analysis of genes involved in glucocorticoid metabolism may be useful in the optimization of treatment of 21-hydroxylase deficiency.