Generating diversity in human glucocorticoid signaling through a racially diverse polymorphism in the beta isoform of the glucocorticoid receptor.

ABSTRACT: Alternative splicing of the human glucocorticoid receptor gene generates two isoforms, hGR? and hGR?. hGR? functions as a dominant-negative regulator of hGR? activity and but also has inherent transcriptional activity, collectively altering glucocorticoid sensitivity. Single-nucleotide polymorphisms in the 3' UTR of hGR? have been associated with altered receptor protein expression, glucocorticoid sensitivity, and disease risk. Characterization of the hGR? G3134T polymorphism has been limited to a relatively small, homogenous population. The objective of this study was to determine the prevalence of hGR? G3134T in a diverse population and assess the association of hGR? G3134T in this population with physiological outcomes. In a prospective cohort study, 3730 genetically diverse participants were genotyped for hGR? G3134T and four common GR polymorphisms. A subset of these participants was evaluated for clinical and biochemical measurements. Immortalized human osteosarcoma cells (U-2 OS), stably transfected with wild-type or G3134T hGR?, were evaluated for receptor expression, stability, and genome-wide gene expression. Glucocorticoid-mediated gene expression profiles were investigated in primary macrophages isolated from participants. In a racially diverse population, the minor allele frequency was 74% (50.7% heterozygous carriers and 23.3% homozygous minor allele), with a higher prevalence in Caucasian non-Hispanic participants. After adjusting for confounding variable, carriers of hGR? G3134T were more likely to self-report allergies, have higher serum cortisol levels, and reduced cortisol suppression in response to low-dose dexamethasone. The presence of hGR? G3134T in U-2 OS cells increased hGR mRNA stability and protein expression. Microarray analysis revealed that the presence of the hGR? G3134T polymorphism uniquely altered gene expression profiles in U-2 OS cells and primary macrophages. hGR? G3134T is significantly present in the study population and associated with race, self-reported disease, and serum levels of glucocorticoids. Underlying these health differences may be changes in gene expression driven by altered receptor stability.

SUBMITTER: Whirledge SD 

PROVIDER: S-EPMC5759773 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature