Healthy glucocorticoid receptor N363S carriers dysregulate gene expression associated with metabolic syndrome.
The glucocorticoid receptor single-nucleotide polymorphism (SNP) N363S has been reported to be associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease. Our aim was to determine how the N363S SNP modifies glucocorticoid receptor signaling in a healthy population of individuals prior to the onset of disease. We examined the function of the N363S SNP in a cohort of subjects from the general population of North Carolina. Eighteen N363S heterozygous carriers and 36 noncarrier, control subjects were examined for clinical and biochemical parameters followed by a low-dose dexamethasone suppression test to evaluate glucocorticoid responsiveness. Serum insulin measurements revealed that N363S carriers have higher levels of insulin, although not statistically significant, compared with controls. Glucocorticoid receptor protein levels evaluated in peripheral blood mononuclear cells from each clinical subject showed no difference between N363S and control. However, investigation of gene expression profiles in macrophages isolated from controls and N363S carriers using microarray, quantitative RT-PCR, and NanoString analyses revealed that the N363S SNP had an altered profile compared with control. These changes in gene expression occurred in both the absence and the presence of glucocorticoids. Thus, our observed difference in gene regulation between normal N363S SNP carriers and noncarrier controls may underlie the emergence of metabolic syndrome, type 2 diabetes, and cardiovascular disease associated with the N363S polymorphism.
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina; and.
Christine M
CM
Jewell
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina; and.
Kevin S
KS
Katen
SRA International Inc., Durham, North Carolina.
Lisa M
LM
Barber
SRA International Inc., Durham, North Carolina.
Crystal
C
Cannon
Clinical Research Unit, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina; and.
Stavros
S
Garantziotis
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina; and cidlows1@niehs.nih.gov.
John A
JA
Cidlowski
D000328:Adult; D000368:Aged; D003907:Dexamethasone / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics* / Q000502:physiology*; D005838:Genotype; D005938:Glucocorticoids / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007328:Insulin / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
D005938:Glucocorticoids; D007328:Insulin; D011965:Receptors, Glucocorticoid; D012313:RNA; D003907:Dexamethasone
cardiovascular disease; insulin resistance; metabolic syndrome; type 2 diabetes