Impact of glucocorticoid receptor gene polymorphisms on the metabolic profile of adult patients with the classical form of 21-hydroxylase deficiency

PLoS One. 2012;7(9):e44893. doi: 10.1371/journal.pone.0044893. Epub 2012 Sep 18.


Background: CAH 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.

Methodology: Sixty-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.

Results: Obesity 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.

Conclusion: In 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Hyperplasia, Congenital / complications
  • Adrenal Hyperplasia, Congenital / genetics*
  • Adrenal Hyperplasia, Congenital / metabolism*
  • Adrenal Hyperplasia, Congenital / physiopathology
  • Adult
  • Biomarkers / metabolism
  • Blood Pressure / genetics
  • Body Mass Index
  • Female
  • Heterozygote
  • Humans
  • Male
  • Metabolic Syndrome / complications
  • Metabolome / genetics*
  • Obesity / complications
  • Polymorphism, Genetic*
  • Receptors, Glucocorticoid / genetics*
  • Waist Circumference / genetics


  • Biomarkers
  • NR3C1 protein, human
  • Receptors, Glucocorticoid

Grant support

This research was supported by grants from FAPESP #09/54238-2, Moreira RPP by Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP #09/54394-4, Bachega TASS by Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq #305117/2009-2 and Mendonca BB by CNPq #301339/2008-9. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.