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Cited by 265Adrenal Hormones and DisordersStress Responses and CortisolEstrogen and related hormone effects

A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo

Huizenga, N. A. T. M.·1998·Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.83.1.144
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Abstract

We investigated whether a polymorphism at nucleotide position 1220, resulting in an asparagine-to-serine change at codon 363 in the glucocorticoid receptor (GR) gene is associated with an altered sensitivity to glucocorticoids. In a group of 216 elderly persons, 13 heterozygotes for the N363S polymorphism were identified by PCR/single strand conformation polymorphism analysis. In 2 dexamethasone (DEX) suppression tests (DSTs), using 1 and 0.25 mg DEX, the circulating cortisol and insulin concentrations were compared between N363S carriers and controls. In the l-mg DST, there were no differences between N363S carriers and controls, with respect to adrenal suppression, but there was a significantly higher (P <0.05) insulin response in N363S carriers. In the 0.25-mg DST, a significantly larger (P <0.05) cortisol suppression and higher (P <0.05) insulin response were seen in N363S carriers. Comparison of blood pressure, body mass index (BMI), and bone mineral density (BMD) between the N363S carriers and controls showed that N363S carriers had a higher (P <0.05) BMI but normal blood pressure. There was an obvious trend towards lower age-, BMI-, and sex-adjusted BMD in the lumbar spine in N363S carriers. GR characteristics measured in 41 controls and 9 N363S carriers in peripheral mononuclear leucocytes showed no differences between N363S carriers and controls, with respect to GR number and ligand binding affinity. However, there was a trend towards greater sensitivity to DEX in the carriers' lymfocytes, in a mitogen-induced cell proliferation assay. In transfection assays, the capacity of the codon 363 variant to activate mouse mammary tumor virus promotor-mediated transcription in COS-I cells was unaltered, when compared with the wild-type GR. We conclude that in 6.0% of our study population, a polymorphism in codon 363 of the GR gene was found. Individuals carrying this polymorphism seemed healthy at clinical examination but had a higher sensitivity to exogenously administered glucocorticoids, with respect to both cortisol suppression and insulin response. Life-long exposure to the mutated allele may be accompanied by an increased BMI and a lowered BMD in the lumbar spine but does not affect blood pressure.

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  • Interindividual sensitivity to glucocorticoids is influenced, in part, by polymorphisms in the glucocorticoid receptor gene, which have been associated with altered receptor function and differential metabolic responses to cortisol.

    “This variability is influenced, in part, by polymorphisms in the glucocorticoid receptor gene, which have been associated with altered receptor function and differential metabolic responses to cortisol (102-108).”

    From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [105]

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Authors
Huizenga, N. A. T. M.
Affiliations
Utrecht University (NL)
Corresponding author
Huizenga, N. A. T. M.
Venue
Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
1998-01-01
Volume
83
Issue
1
Pages
144-151
ISSN
0021-972X (ISSN-L)
DOI
10.1210/jc.83.1.144
OpenAlex
W4235407402
Cited by
265
References
2
Citations by year
2025: 1 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 8 · 2014: 3 · 2013: 9 · 2012: 16
FWCI
7.68
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
glucocorticoid receptor, N363S polymorphism, genetic polymorphism, glucocorticoid sensitivity, dexamethasone suppression test, cortisol suppression, insulin response, bone mineral density, body mass index, lymphocyte proliferation, ligand-receptor binding affinity, older adults, gene-environment interaction, glucocorticoid exposure, transcriptional activation

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