Characterization of a promoter polymorphism in the glucocorticoid receptor gene and its relationship to three other polymorphisms.
OBJECTIVE
Sensitivity to glucocorticoids within the normal population is highly variable and partly determined by polymorphisms in the glucocorticoid receptor (GR) gene (NR3C1). We investigated the exact sequence alteration of a TthIIII polymorphism in the GR gene, whether it is associated with glucocorticoid sensitivity, and its relationship to 3 polymorphisms of the GR gene (N363S, BclI, ER22/23EK).


METHODS
Two dexamethasone (DEX) suppression tests were performed with 1 and 0.25 mg DEX, respectively.


METHODS
We genotyped a random subgroup of 209 participants of the Rotterdam Study, a population-based study in the elderly.


METHODS
Anthropometric parameters, cortisol, insulin and glucose levels, and lipid concentrations were measured.


RESULTS
We identified the TthIIII polymorphism as a C to T mutation, 3807 bp upstream from the mRNA start site. We found 39.7% CC-carriers, 44.5% CT-carriers, and 15.8 % TT-carriers. No differences were found between TthIIII genotypes in sensitivity to DEX, baseline cortisol, insulin, glucose or cholesterol levels, or in anthropometric variables. However, all ER22/23EK-carriers also carried the TthIIII T-allele, and carriers of both these polymorphisms had a significantly smaller cortisol suppression after 1 mg DEX, lower fasting insulin levels, and lower total and low-density lipoprotein (LDL) cholesterol levels than TthIIII T carriers without the ER22/23EK variant and noncarriers. No interaction was found between the TthIIII variant and N363S or BclI polymorphisms.


CONCLUSIONS
The TthIIII polymorphism is not functional by itself. However, the ER22/23EK polymorphism is without exception linked to the TthIIII T polymorphism and this haplotype is associated with a relative resistance to glucocorticoids, and a healthy metabolic profile.
van Rossum
Elisabeth F C
EF
Department of Internal Medicine, Erasumus Medical Center, Rotterdam, The Netherlands. e.vanrossum@erasmusmc.nl
Roks
Petronella H M
PH
de Jong
Frank H
FH
Brinkmann
Albert O
AO
Pols
Huib A P
HA
Koper
Jan W
JW
Lamberts
Steven W J
SW
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001786:Blood Glucose / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D017422:Sequence Analysis, DNA
D001786:Blood Glucose; D008078:Cholesterol, LDL; D005938:Glucocorticoids; D007328:Insulin; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D002784:Cholesterol; D006854:Hydrocortisone