Impact of Glucocorticoid Receptor Gene Polymorphisms on the Metabolic Profile of Adult Patients with the Classical Form of 21-Hydroxylase Deficiency

Abstract

BackgroundCAH patients have an increased risk of cardiovascular disease, and it remains unknown if lifelong glucocorticoid (GC) treatment is a contributing factor. In the general population, glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of CAH patients.MethodologySixty-eight adult patients (34SV/34SW) with a mean age of 28.4±9 years received dexamethasone (mean 0.27±0.11 mg/day) to obtain normal androgen levels. SW patients also received fludrocortisone (50 µg/day). Metabolic syndrome (MetS) was defined by the NCEP ATPIII criteria and obesity by BMI ≥30 kg/m2. NR3C1 alleles were genotyped, and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis.ResultsObesity and MetS were observed in 23.5% and 7.3% of patients, respectively, and were not correlated with GC doses and treatment duration. BMI was positively correlated with blood pressure (BP), triglycerides (TG), LDL-c levels and HOMA-IR and inversely correlated with HDL-c levels. BclI and A3669G variants were found in 26.4% and 9.6% of alleles, respectively. Heterozygotes for the BclI polymorphism presented with higher BMI (29 kg/m2±5.3 vs. 26 kg/m2±5.3, respectively) and waist circumference (89 cm±12.7 vs. 81 cm±13, respectively) compared to wild-type subjects. Hypertension was found in 12% of patients and heterozygotes for the BclI polymorphism presented higher systolic BP than wild type subjects. Low HDL-c and high TG levels were identified in 30% and 10% of patients, respectively, and were not associated with the NR3C1 polymorphisms. A3669G carriers and non-carriers did not differ.ConclusionIn addition to GC therapy, the BclI GR variant might play an important role in obesity susceptibility in CAH patients. Genotyping of GR polymorphisms could result in the identification of a subgroup at risk patients, allowing for the establishment of personalized treatment and the avoidance of long-term adverse consequences.

Associations Between Polymorphisms in the Glucocorticoid-Receptor Gene and Cardiovascular Risk Factors in a Chinese Population

“…Of the 19 makers studied, associations with 5 markers were evident; associations with the other 14 makers were nonsignificant. Although the N363S, Bcl I, ER22/23EK, and A3669G polymorphisms of the GR gene have been identified among white and African-American populations, 23 – 25 only the Bcl I polymorphism was found in our study. The frequency of the minor allele of the Bcl I polymorphism in the present study was similar to that among other Asian populations and among Western populations.…”

Obesity and Familial Predisposition Are Significant Determining Factors of an Adverse Metabolic Profile in Young Patients with Congenital Adrenal Hyperplasia

“…However, these discordant results could also be related to the different approaches to hormonal control; in the latter study, the serum 17-OHP levels were maintained at <30 nmol/l, and in our cohort, we maintained normal androgen levels according to age and sex [28]. Comparable findings were identified in our previous study involving adult CAH patients, in which there was no correlation among BMI, GC dose and duration of therapy [29]. …”

Determining clinical and biological indicators for health outcomes in adult patients with childhood onset of congenital adrenal hyperplasia

“…This should be evaluated further and more precisely. Another explanation could be the presence in some patients of particular glucocorticoid receptor polymorphisms, which have been shown to be associated with poor metabolic state in CAH patients (37). Another interesting finding is the demonstration that clinical form of CAH (CF vs NCF diagnosed in childhood) does not seem to be a determining factor of adverse outcomes if the patients have controlled disease.…”