GLUCOCORTICOIDS AND MOOD

Clinical Features Associated with

Glucocorticoid Receptor Polymorphisms
An Overview
Laura Manenschijn, Erica L. T. van den Akker,
Steven W. J. Lamberts, and Elisabeth F. C. van Rossum
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands

The glucocorticoid receptor (GR) is crucial for the effects of glucocorticoids (GCs).
Several polymorphisms of the GR are associated with altered sensitivity to GCs.
For the ER22/23EK polymorphism, a relative GC resistance has been demonstrated.
In vivo, this was suggested by a smaller response to a dexamethasone suppression
test (DST), whereas in vitro experiments showed a diminished transactivational activ-
ity. The associated features of ER22/23EK carriers consist of favorable metabolic and
body compositional conditions. In elderly subjects this polymorphism was associated
with longevity and decreased risk of dementia. Interestingly, recent studies also showed
an increased risk of major depression. In contrast, the N363S polymorphism was re-
ported to be associated with an enhanced sensitivity to GCs, as was demonstrated by
a DST. This polymorphism has also been associated with increased body mass index
(BMI) and LDL-cholesterol levels, as well as increased risk of cardiovascular disease.
However, additional studies yielded conflicting results, showing no associations with
being overweight. The BclI polymorphism is also associated with increased GC sen-
sitivity. In addition, associations with increased abdominal fat mass, Crohn’s disease
and, remarkably, major depression have been reported. Another GR polymorphism,
located in exon 9β, is associated with increased expression and stabilization of the
dominant negative splice variant GR-β. Carriers of this polymorphism displayed a
relative GC resistance in vitro as evidenced by diminished transrepressional activity,
which is important for the immune system and inflammation. Associations have been
found with increased inflammatory parameters, cardiovascular disease, and rheuma-
toid arthritis. In this article, studies concerning these clinically relevant GR variants are
discussed.

Key words: glucocorticoid receptor (GR); ER22/23EK polymorphism; BclI polymor-

phism; N363S polymorphism; exon 9β

Introduction high levels of cortisol are associated with neu-

Glucocorticoids (GCs) have diverse effects
in the human body and are essential for sur-
vival. GCs affect lipid and glucose metabolism,
immunosuppressive and anti-inflammatory ac-
tions, growth, and brain function. Chronically
Address for correspondence: Elisabeth F.C. van Rossum, M.D., Ph.D.,
Department of Internal Medicine, Room D400, Section of Endocrinology,
Erasmus Medical Center, Rotterdam, the Netherlands. Voice: +31-10-
7040704. e.vanrossum@erasmusmc.nl
Glucocorticoids and Mood: Ann. N.Y. Acad. Sci. 1179: 179–198 (2009).
doi: 10.1111/j.1749-6632.2009.05013.x  c 2009 New York Academy of Sciences.
ropsychiatric disorders and cognitive impair-
ment. Cortisol is the main GC in humans.
The secretion of GCs is under control of the
hypothalamic-pituitary-adrenal (HPA) axis.1–3
The negative feedback system of the HPA axis
is induced by cortisol itself and affects both
the hypothalamus as well as the pituitary.3,4
This feedback mechanism can be tested by a
dexamethasone suppression test (DST), where
cortisol levels are measured in the morning
after 0.25 mg or 1 mg dexamethasone is ad-
ministered at 2300 h the day before. The next

179
180
morning, cortisol levels are suppressed because
of the negative feedback system.5
At the tissue level, the activation and inac-
tivation of cortisol is intracellularly regulated
by the enzyme 11β-hydroxysteroid dehydroge-
nase (11β-HSD). 11β-HSD I acts as a reduc-
tase by converting inactive cortisone into active
cortisol. 11β-HSD II converts cortisol into cor-
tisone.6,7 11β-HSD I and 11β-HSD II regulate
cortisol availability at the tissue level and con-
tribute to tissue-specific effects.
In general, the effects of GCs are medi-
ated by the glucocorticoid receptor (GR). The
GR gene (NR3C1) is located on chromosome
5 and is a member of the nuclear receptor
family. It has a three-domain structure: an
amino-terminal transactivating domain, which
directs transactivation of target genes; a DNA-
binding domain, interacting with glucocorti-
coid response elements (GRE) in the DNA;
and a carboxy-terminal ligand-binding do-
main, which contains specific steroid and heat
shock protein binding sites.8
In the unliganded form, the GR is present in
the cytoplasm. After binding of cortisol, a con-
formational change occurs, which leads to dis-
sociation of the receptor from a large complex
of proteins. This activated, ligand-bound re-
ceptor then translocates to the nucleus, where it
acts as a transcription factor to regulate gene ex-
pression.9 Several main mechanisms of action
are known. First, GR can activate or repress
gene expression by interacting with specific
DNA sequences, the GREs, which are present
in the promoter regions of steroid-responsive
genes. This mechanism is called transactiva-
tion. The side-effects of GC treatment are
mainly mediated by transactivation.10 When
binding to negative GREs, transrepression of
target genes occurs. The second mechanism of
GR action is through interaction with other
transcription factors such as activator protein 1
or nuclear factor κ B, thereby repressing their
transcriptional activity, which results in inhi-
bition of pro-inflammatory transcription fac-
tors. These transrepressive effects of GR are
the main mechanism that accounts for anti-
Annals of the New York Academy of Sciences
inflammatory effects of GCs and explains why
they are extensively used in the treatment of
inflammatory and autoimmune diseases.10 A
third mechanism involves nongenomic activa-
tion. GCs can have rapid effects on inflamma-
tion that are not mediated by changes in gene
expression. This involves the activation of en-
dothelial nitric oxide synthetase.11
GR mutations leading to loss of func-
tion and generalized GC resistance are rare.
Generalized cortisol resistance is character-
ized by hypercortisolism without Cushingoid
features. In such conditions, negative feed-
back on the HPA axis is reduced due to
diminished GC sensitivity, resulting in higher
cortisol secretion by the adrenal glands to
keep balance between need and produc-
tion. However, due to increased adrenocor-
ticotrophic hormone (ACTH) levels, adrenal
production of mineralocorticoids is also in-
creased, causing the symptoms of hyperten-
sion and hypokalemia. In addition, due to
the compensatory elevated cortisol levels, the
capacity of the cortisol inactivating enzyme
11β-HSD II is overridden, which also yields
mineralocorticoid effects of GCs, leading to hy-
pertension and hypokalemia. As a result of the
elevated ACTH levels, adrenal androgen lev-
els are also increased, causing—in particular
in females—acne, hirsutism, virilisation, male
pattern of baldness, menstrual irregularity, and
infertility.12
A large number of polymorphisms in the
GR gene are known. A few of these poly-
morphisms are functionally relevant. The
TthIII I (rs10052957), ER22/23EK (rs6189
and rs6190), N363S (rs6195), BclI (rs41423247)
and GR-9β (rs6198) have not only been associ-
ated with changes in GC sensitivity or altered
cortisol levels, but some are also associated with
differences in body composition, metabolic pa-
rameters, autoimmune diseases and cardiovas-
cular disease. A schematic overview of the GR
gene including these polymorphisms is shown
in Figure 1. In this review the clinical features
associated with these GR polymorphisms will
be discussed.
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms
Figure 1. Schematic overview of the GR gene, showing the polymorphisms discussed in
this review.
The TthIII I Polymorphism
of the GR Gene
The TthIII I polymorphism is a restriction
fragment length polymorphism (RFLP), caused
by a C → T change 3807 bp upstream of
the GR mRNA start site. Rosmond et al. pre-
viously showed that this polymorphism is as-
sociated with elevated diurnal cortisol levels.13
However, the TthIII I polymorphism is partially
linked to the ER22/23EK polymorphism with
carriers of the latter polymorphism all carry-
ing the TthIII I minor allele. In those indivi-
duals GC sensitivity appeared to be decreased,
as measured by a low dose DST. In contrast,
in carriers of the TthIII I variant allele without
the ER22/23EK polymorphism, GC sensitiv-
ity was unaltered, suggesting that the TthIII I
polymorphism may not be functional by
itself.14
Recently, associations with unipolar and
bipolar depression have been described.
Zobel et al. described that the frequency of ho-
mozygous carriers of the TthIII I polymorphism
was higher in a group of unipolar depression
patients.15 Associations with hippocampal and
181
amygdala size were also reported. Left hip-
pocampal size was significantly decreased in
homozygous carriers of the TthIII I polymor-
phism, whereas left amygdala volume was also
decreased in homozygous carriers of this poly-
morphism. Right hippocampal volume was not
associated with the TthIII I polymorphism, and
right amygdala volume was only borderline
significantly decreased in homozygous carri-
ers. Smaller hippocampal volumes have been
reported to be associated with an increased
risk of developing depression.16 Therefore, the
smaller hippocampal volumes in TthIII I poly-
morphism carriers are consistent with the re-
lationship between the TthIII I polymorphism
and unipolar depression.15 In contrast, a lower
frequency of heterozygous TthIII I polymor-
phism carriers was found in bipolar disorder
patients.17
The ER22/23EK Polymorphism
of the GR Gene
This polymorphism is located in the trans-
activation domain of the GR gene. In both of
182
two adjacent codons (codon 22 and 23), a sin-
gle nucleotide polymorphism (SNP) has been
identified. The exact sequence alteration at the
DNA level is GAG AGG to GAA AAG, which
is translated in protein: glutamic acid-arginine
(E-R) to glutamic acid-lysine (E-K). Since these
SNPs are fully linked and may, due to their
close locations, both be relevant for the under-
lying mechanism of an altered GR effect, these
variants often have been studied as a combined
polymorphism.18
Previously, it has been found that the
ER22/23EK polymorphism is associated with
relative GC resistance, as shown by less sup-
pression of cortisol levels after 1 mg of dex-
amethasone in vivo and a reduction of trans-
activating capacity in transfection experiments
and in peripheral blood mononuclear lym-
phocytes of carriers.19,20 In accordance with
a relative systemic GC resistance, associations
were found between the ER22/23EK poly-
morphism and lower fasting insulin levels, in-
creased insulin sensitivity, and lower total and
low-density lipoprotein (LDL)-cholesterol lev-
els.19 This favorable metabolic profile might
yield a lower risk of developing type 2 diabetes
mellitus or cardiovascular disease. In a large
group of Dutch patients with familial hyperc-
holesterolemia who are known to have a very
high risk of cardiovascular disease, a gender-
specific risk modification was observed, with
a trend in males showing protection, while in
females, there was a slightly increased risk of
cardiovascular disease.21 The observation that
in a normal Dutch population the frequency of
ER22/23EK carriers was higher in the oldest
members of an elderly population suggested
a survival effect. This concept was strength-
ened by finding an association with longevity
in another study in elderly healthy men, in
which 19.2% of the noncarriers died in a
follow-up period of 4 years, whereas none of
the ER22/23EK polymorphism carriers died
in the same timeframe. In this male popula-
tion, we also found lower C-reactive protein
(CRP) levels in ER22/23EK carriers as well
as a trend for lower total and LDL-cholesterol
Annals of the New York Academy of Sciences
levels in elderly carriers of the ER22/23EK
polymorphism, which is in line with the previ-
ously observed beneficial cardiovascular profile
with respect to metabolic factors and inflamma-
tion.22 In contrast, in 2006, Kuningas et al.23
published a study in which the various GR
polymorphisms were determined in a group
of participants over 85 years old. Carriers of
the ER22/23EK polymorphism were found to
have significantly higher levels of HbA1c than
noncarriers. In addition, a trend toward higher
CRP levels in carriers of this polymorphism was
also observed. As previously suggested, the dis-
crepancy with respect to the metabolic findings
might be due to age differences or explained by
a type 1 error (false positive finding).23
Studies in younger individuals showed dif-
ferences in anthropometric parameters and
body compositions between carriers and non-
carriers of the ER22/23EK polymorphism.
Male carriers of this polymorphism were found
to be taller than noncarriers.24 Kuningas et al.
confirmed this association of the ER22/23EK
with increased height.23
Interestingly, in a group of preterm-born
children, Finken et al. reported that chil-
dren carrying the ER22/23EK polymorphism
showed complete catch-up growth between the
age of 3 months and 1 year. The ER22/23EK
children had from the age of 1 year a taller
stature than noncarrying preterm children.
The authors also observed in this study pop-
ulation that fasting insulin levels were lower
in the ER22/23EK carriers.25 Both the find-
ings of catch-up growth and lower insulin lev-
els support the concept that ER22/23EK car-
riers may be relatively resistant to the (central
and systemic) effects of GCs. No associations
with body mass index (BMI) or fat mass were
observed, but lean body mass was significantly
higher in males carrying the ER22/23EK poly-
morphism.24 Muscle strength was also signi-
ficantly greater in these men. In females, no
differences in BMI were found. However, a
trend toward a smaller waist circumference
was observed in female ER22/23EK-carriers,
which is of particular interest since it could be
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms
expected that a subtle decreased GC effect at
the abdominal region would result in a smaller
waist.
GCs are well known to repress the im-
mune system through various mechanisms and
are widely used as treatment for many au-
toimmune diseases.26 Consequently, associa-
tions between the ER22/23EK polymorphism
and several autoimmune or inflammatory dis-
eases were studied. van Winsen et al. showed
that the ER22/23EK polymorphism was as-
sociated with a more aggressive disease course
in multiple sclerosis patients, which was shown
by a more destructive disease process both
clinically and on magnetic resonance imag-
ing.27 In contrast, no associations were found
between the ER22/23EK polymorphism and
Graves’ ophthalmopathy, inflammatory bowel
diseases (IBDs), and rheumatoid arthritis.28–31
Thus, evidence that the ER22/23EK poly-
morphism is related to autoimmune diseases
of inflammatory diseases is rather limited. In-
terestingly, in vitro studies showed that the
ER22/23EK polymorphism resulted in a sig-
nificant reduction of transactivating capacity.20
In line with the predominantly negative clin-
ical findings with respect to associations with
autoimmune diseases, no alterations in trans-
repressional activity, which is mainly involved
in the immune system and inflammation, was
demonstrated for the ER22/23EK variant.20
Interestingly, heterozygous ER22/23EK poly-
morphism carriers had an 80% increased risk
of persistent Staphylococcus aureus (S. aureus) nasal
carriage. Theoretically, slightly higher cortisol
levels in ER22/23EK polymorphism carriers
could lead to an increased transrepression and
thereby an increased suppression of the im-
mune system.32
Associations have been found between ele-
vated cortisol levels and cognitive impairment
and dementia. High cortisol levels have been
associated with a more rapid decline in cog-
nitive function in healthy elderly as well as in
patients with Alzheimer’s disease.33–35 Relative
GC resistance as a result of the ER22/23EK
polymorphism could be beneficial in reducing
183
the risk of developing dementia or cognitive
impairment with aging. In a large Dutch pop-
ulation in the elderly (aged over 55 years), we
indeed found that dementia and white mat-
ter lesions are less frequent in carriers of the
ER22/23EK polymorphism. Additionally, we
found that carriers of this polymorphism had
a better cognitive performance with respect to
cognitive speed tasks. In accordance with a pos-
sible diminished GC effect at the cerebral tis-
sues and/or vascular system due to a decreased
GR activity, ER22/23EK carriers also showed
less progression of subcortical lesions.36
Since it has been recognized that the major-
ity of severely depressed inpatients show HPA
axis disturbances, which are in concordance
with a GR resistance, it is of particular interest
that recent studies have been published con-
cerning associations between the ER22/23EK
polymorphism and depression. In German
Caucasian depressed patients, a higher sus-
ceptibility to recurrently develop major de-
pression was associated with ER22/23EK
polymorphism carriage, and carriers of this
polymorphism responded faster to antidepres-
sant treatment.37 van West et al. also described a
higher frequency of the ER22/23EK polymor-
phism in a Swedish group of major depressive
patients.38 No associations were found between
the ER22/23EK polymorphism and bipolar
disorder.17 Table 1 shows an overview of the
associations found between the ER22/23EK
polymorphism and clinical parameters.
Recently, the mechanism concerning the ob-
served relative GC resistance in ER22/23EK
polymorphism carriers was studied at the
molecular level. It was shown that carriers of
the ER22/23EK polymorphism had a higher
expression of the GR translational variant GR-
A.39 Interestingly, in this context, Yudt and
Cidlowski40 reported that there are at least
two translational variants of the GR. The first
variant, GR-A, results from translation of the
GR mRNA from the first AUG codon. The
second variant, GR-B, results from transla-
tion of the GR mRNA from the second AUG
codon. The GR-B protein is transcriptionally
184 Annals of the New York Academy of Sciences

TABLE 1. Data from Studies that Investigated the Association between the ER22/23EK-Polymorphism
of the Glucocorticoid Receptor Gene and Clinical Parameters
Association with the
Reference Population ER22/23EK polymorphism

van den Akker 3851 Dutch elderly, 678 carriers of nasal S. • 80% increased risk of S. aureus nasal carriage
et al.32 aureus, 2804 noncarriers
Boyle et al.28 95 Hungarian patients with GO and 160 • No association with GO
healthy controls
Decorti et al.30 57 young patients with IBD • No association with IBD
De Iudicibus et al.29 119 young patients with IBD and 100 • No association with IBD
healthy blood donors
Donn et al.31 198 RA patients and 393 control subjects • No association with RA
Finken et al.25 249 19-year-old subjects born at a • Complete catch-up growth in preterm-born
gestational age less than 32 weeks children
• Taller stature in preterm-born children
during follow-up
Koeijvoets et al.21 2024 patients with heterozygous FH • Sex-specific risk modification of
cardiovascular disease: in males, a relative
protection, and in females, a slightly
increased risk
Kuningas et al.23 563 Dutch subjects of age > 85 years • Higher levels of HbA1c
• Trend toward higher CRP levels
• No association with MI, claudication
intermittens and stroke
• Taller stature
van Rossum et al.19 202 healthy elderly subjects • Less suppression after dexamethasone,
indicating GC resistance
• Lower fasting insulin levels, increased
insulin sensitivity and lower total and
LDL-cholesterol levels
• Higher frequency of carriage in the older
half of the population
van Rossum et al.22 402 elderly men • Lower CRP levels
• Trend for lower LDL- and total cholesterol
levels
• Longevity
van Rossum et al.24 350 subjects followed from the age of 13 • Taller stature in young men
until 36 years • No difference in BMI in men
• Higher lean body mass and muscle strength
in men
• Trend toward smaller waist circumference
in women
van Rossum et al.36 7045 elderly subjects, MRI scan obtained • Lower risk of dementia
in a subgroup of 1077 subjects
• Better cognitive performance (with respect
to speed tasks)
• Lower risk of developing white matter
lesions
van Rossum et al.37 490 patients with major depression and • Association with recurrent major depression
496 controls • Faster response to antidepressant therapy
Continued
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms 185

TABLE 1. Continued
Association with the
Reference Population ER22/23EK polymorphism

• Tendency toward better cognition (divided

attention test) during a depressive episode
Spijker et al.17 241 patients with bipolar disorder and 532 • No associations with bipolar disorder
controls
van West et al.38 180 Belgian patients and 134 Swedish • Association with major depression in the
patients with major depression and 354 Swedish sample but not in the Belgian
controls sample
van Winsen et al.27 257 MS patients and 178 healthy controls • More aggressive disease course in MS
patients
Abbreviations: S. aureus, Staphylococcus aureus; GO, Graves’ ophthalmopathy; IBD, inflammatory bowel disease; RA,
rheumatoid arthritis; FH, familial hypercholesterolemia; HbA1c, subtype of hemoglobin after glucose binding; CRP,
C-reactive protein; MI, myocardial infarction; GC, glucocorticoid; LDL, low-density lipoprotein; BMI, body mass
index; MRI, magnetic resonance imaging; MS, multiple sclerosis.

more active than the GR-A protein.40 It is
likely that the higher expression of GR-A we
showed in ER22/23EK polymorphism carri-
ers leads to decreased expression of the more
transcriptionally active GR-B protein by al-
tering the secondary structure at the mRNA
level. This probably results in ribosomal leak-
age yielding more of the GR-A translation vari-
ant. The higher intracellular concentrations
of the less active variant of the GR could be
(one of) the mechanism(s) underlying the rela-
tive GC resistance caused by the ER22/23EK
polymorphism.39
The N363S Polymorphism
of the GR Gene
The N363S polymorphism is located in
codon 363 of exon 2 and results from an
AAT → AGT nucleotide change. This change
yields an amino acid alteration from asparagine
(N) to serine (S). This polymorphism shows
an increased trans-activating capacity in vitro
and is associated with increased sensitivity
to GCs in vivo, as was shown by increased
cortisol suppression after a 0.25 mg DST
in a group of 216 Dutch elderly individu-
als and in 112 German individuals.18,20,41 In
this study of the elderly, an association was
also observed between the N363S polymor-
phism and a higher BMI and a tendency
toward decreased bone mineral density in tra-
becular bone. Since then, several other studies
have investigated the relationship between the
N363S polymorphism and BMI. Table 2 shows
an overview of these associations. Lin et al. con-
firmed the association between the N363S vari-
ant and increased BMI and demonstrated an
allele-dosage effect of this association.42
Dobson et al. found an increased waist-to-
hip ratio (WHR) in male carriers of the N363S
polymorphism but no associations with BMI,
serum lipid levels, and glucose tolerance sta-
tus.43 However, controversy about the relation-
ship of the N363S and obesity arose when
additional studies reported no association be-
tween the N363S with BMI, WHR, and weight
gain.44–46 However, Di Blasio et al. showed, in a
population of Italian obese men and women, an
association between the N363S polymorphism
with increased BMI. Interestingly, in this popu-
lation, carriers of both the N363S and the BclI
polymorphism seemed to have higher choles-
terol levels.47 Kuningas et al. also reported in-
creased concentrations of LDL-cholesterol and
triglyceride levels in N363S-carriers in a pop-
ulation of Dutch subjects aged 85 years and
over.23 In contrast, Buemann et al. found that
male carriers of the N363S polymorphism with
186 Annals of the New York Academy of Sciences

TABLE 2. Data from Studies that Investigated the Association between the N363S Polymorphism of the
Glucocorticoid Receptor Gene and Clinical Parameters
Association with the
Reference Population N363S polymorphism

Bonifati et al.51 48 patients with DMD • Possible association with higher age of
loss of ambulation
Boyle et al.28 95 Hungarian patients with GO and 160 • No association with GO
healthy controls
Buemann et al.48 208 men with juvenile onset obesity and • Association with lower whole body fat
299 non-obese men percentage in men with juvenile-onset
obesity
Decorti et al.30 57 young patients with IBD • No association with IBD
De Iudicibus 119 young patients with IBD and 100 • No association with IBD
et al.29 healthy blood donors
Di Blasio et al.47 185 obese women, 94 obese men • Increased BMI, resting energy
expenditure and food intake
• Interaction with the BclI polymorphism:
higher cholesterol levels and trend for
higher blood pressure
Dobson et al.43 135 men and 240 women • Increased WHR in men
Donn et al.31 198 RA patients and 393 control subjects • No association with RA
Echwald et al.45 741 obese Danish men and 854 non-obese • No association with BMI, WHR, or
controls weight gain
Halsall et al.44 491 subjects • No associations with BMI
Huizenga et al.41 216 Dutch men and women • Increased cortisol suppression after DEX
• Increased insulin response to DEX
• Increased BMI
Kuningas et al.23 563 Dutch subjects of age > 85 years • Higher concentrations of LDL and
triglycerides
Lin et al.42 195 normotensive controls and 124 • Increased BMI (allele-dosage effect)
hypertensive subjects
Lin et al.88 437 Anglo-Celtic CAD patients and 302 • Association with CAD
controls • Elevated cholesterol, triglycerides and
total cholesterol/HDL ratio
Lin et al.89 951 Anglo-Celtic/Northern European • Association with obesity and overweight
subjects: 152 obese, 356 type 2 diabetes, • No association with hypertension or type
141 hypertensive, 302 controls 2 diabetes
Luczay et al.52 200 CAH children • Milder genital virilisation at birth in
CAH females
Rosmond et al.46 284 Swedish men • No association with BMI
• No association with sensitivity to GCs
Roussel et al.90 369 French Caucasians with type 2 diabetes • Higher prevalence of overweight
• Higher body weight
• Higher BMI in men
van Winsen et al.27 257 MS patients and 178 healthy controls • No association with MS
Wüst et al.53 112 healthy men • Enhanced salivary cortisol response after
psychosocial stress
• Trend for increased cortisol suppression
after DEX
Abbreviations: DMD, Duchenne muscular dystrophy; GO, Graves ophthalmopathy; IBD, inflammatory bowel
disease; BMI, body mass index; WHR, waist-to-hip ratio; RA, rheumatoid arthritis; GC, glucocorticoid; DEX, dex-
amethasone; LDL, low-density lipoprotein-cholesterol; CAD, coronary artery disease; HDL, high-density lipoprotein-
cholesterol; CAH, congenital adrenal hypoplasia; MS, multiple sclerosis.
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms
juvenile-onset obesity had a lower whole body
fat percentage at adult age than noncarriers of
this polymorphism, as well as increased insulin
sensitivity.48
In 2006, Marti et al. published a meta-
analysis on the effect of the N363S
polymorphism on human obesity.49 In this
meta-analysis they used two novel study popu-
lations from Spain and Germany and the pub-
lished data from 12 studies with a total num-
ber of 5909 subjects. In this meta-analysis they
found a significantly higher BMI in N363S
polymorphism carriers in the group of partic-
ipants with BMI values below 27 kg/m2 from
one-population studies. In the two-population
studies (nonobese versus obese subjects) they
found no statistically significant differences in
BMI between carriers and noncarriers of the
N363S polymorphism in both groups. When
only the novel data from the Spanish and Ger-
man study populations were used, they found
that the pooled BMI was decreased and statis-
tically significant in carriers of the N363S poly-
morphism. The overall risk of obesity linked to
the N363S polymorphism was not significant
in this meta-analysis.49
Theoretically, carriers of the N363S poly-
morphism could be expected to be less prone
to autoimmune diseases since they may be
more sensitive to GCs. However, several pre-
vious studies concerning the relationship be-
tween the N363S polymorphism and autoim-
mune diseases have been published and yielded
no associations. van Winsen et al. found no asso-
ciations between the N363S polymorphism and
disease onset, age of onset and disease course in
multiple sclerosis patients.27 Two studies in pa-
tients with IBD showed no association between
the N363S polymorphism and Crohn’s disease
or ulcerative colitis.29,30 Donn et al. found no
association between the N363S polymorphism
and rheumatoid arthritis,31 and no associa-
tions were found between this polymorphism
and opthalmopathy in patients with Graves’
disease.28
In contrast, recent data suggest a lower risk of
rheumatoid arthritis in N363S carriers, as was
187
shown in a large Dutch case–control study.50
Also, in patients with Duchenne muscular
dystrophy (DMD) treated with GCs, Bonifati
et al.51 demonstrated a trend toward an associ-
ation between the N363S polymorphism and
the age of loss of ambulation. The observation
that the age of loss of ambulation in N363S car-
riers was higher than in noncarriers, suggesting
a better response to GCs in DMD patients car-
rying the N363S variant. However, the N363S
polymorphism was only found in three patients;
therefore, these results should be cautiously in-
terpreted and replicated.51
In a study published by Luczay et al.,52 as-
sociations between the N363S polymorphism
and congenital adrenal hypoplasia (CAH) were
investigated in a population of 200 Hungarian
CAH patients. They found that female carriers
of the N363S polymorphism had milder gen-
ital virilisation at birth than noncarrier CAH
females, possibly reflecting a compensatory re-
duction in ACTH production as a result of in-
creased GC sensitivity. No significant difference
in substitution doses, hormonal or auxiologic
parameters between carriers and noncarriers
was observed.52
In addition to somatic effects of this GR
variant, psychological associations have also
been found. Wüst et al. demonstrated associa-
tions between the N363S polymorphism and
an enhanced salivary cortisol response after
psychosocial stress, and a trend for increased
cortisol suppression after dexamethasone.53
The molecular mechanism concerning in-
creased sensitivity to GCs is unknown. In 2005,
Russcher et al. found a significant increase in
transactivation of the GC response element
luciferase (GRE-LUC) reporter gene by the
N363S variant constructed GR.20 In a study
published by Jewell and Cidlowski,54 this in-
crease in transactivation was not found. Jew-
ell and Cidlowski also did not find a dif-
ference between the N363S polymorphism
and wild-type GR in the ability to undergo
hormone-mediated downregulation. Interest-
ingly, in the absence and presence of dexam-
ethasone, micro-array data showed that the
188
N363S polymorphism can regulate a novel set
of genes in comparison to wild-type GR. This
suggests that the N363S phenotype may be
the result of differential effects on gene regu-
lation.54 However, the exact mechanisms and
specific genes involved in this mechanism have
not been clarified yet.
The Bcl I Polymorphism
of the GR Gene
The BclI polymorphism was first described
as an RFLP consisting of a fragment of 2.3 kb
and a fragment of 4.5 kb.55 The nucleotide
alteration was identified as a C → G substi-
tution, 646 nucleotides downstream from exon
2, yielding fragments of 2.2 kb and 3.9 kb.56
Many studies have been published concern-
ing the role of the BclI polymorphism in obe-
sity and autoimmune or inflammatory diseases.
Table 3 shows an overview of the published
articles.
After 1 mg dexamethasone, as well as af-
ter 0.25 mg dexamethasone, carriers of the G-
allele had lower cortisol levels, suggesting an
increased sensitivity to GCs with respect to the
adrenal negative feedback to the pituitary. This
feedback is mediated by the GR.
In line with an increased sensitivity to GCs,
several studies described positive associations
with (abdominal) obesity. In young individu-
als, increased BMI, WHR, and abdominal fat
were found in carriers of the G-allele.57–60 In
contrast, in a group of elderly Dutch individu-
als we found lower BMI and WHR in carriers
of the BclI polymorphism and a trend toward
a lower lean body mass.56 Our finding of lower
BMI in elderly carriers of the BclI polymor-
phism could be explained by the lower lean
body mass we found in this population, sug-
gesting that BMI is lower due to muscle atro-
phy, as total fat mass did not differ between
carriers and noncarriers of the BclI polymor-
phism. However, other studies found no asso-
ciation with obesity.23,61,62 Panarelli et al. did
not find an association between BMI and the
Annals of the New York Academy of Sciences
BclI polymorphism, but they did find an in-
creased sensitivity in vivo to budesonide in ho-
mozygous carriers of the BclI polymorphism,
suggesting an increased sensitivity to GCs.63
Weaver et al. also found no association with
obesity, but higher insulin levels were found in
obese carriers of the BclI polymorphism, which
also supports the suggestion of increased GC
sensitivity in BclI carriers.62 An association with
hypertension is also described.64 No associa-
tions were found with cardiovascular disease
risk factors, such as total and LDL cholesterol,
triglycerides, and HbA1c,23 although in carri-
ers of both the BclI G-allele and the N363S
polymorphism, cholesterol levels seemed to be
elevated.47
In several studies, associations between the
BclI polymorphism and autoimmune diseases
have been found. In patients with Graves’ oph-
thalmopathy, an association was found between
the BclI polymorphism and the American Thy-
roid Association (ATA) stage, which is a mea-
sure of severity of ophthalmopathy in patients
with Graves’ disease.28,65 The frequency of BclI
was higher in patients with ATA stage I-II,
which indicates mild ophthalmopathy, com-
pared with those with ATA III-IV (severe
ophthalmopathy). This suggests that the BclI
polymorphism is associated with lower sus-
ceptibility for developing severe ophthalmopa-
thy in patients with Graves’ disease. This
might be explained by enhanced sensitiv-
ity to endogenous GCs, and subsequently
increased suppression of immune and in-
flammatory reactions. Decorti et al. deter-
mined the BclI polymorphism in patients
with IBD. Notably, they found a higher
frequency of BclI in patients with Crohn’s
disease compared to healthy controls, but not
in patients with ulcerative colitis.30 De Iudi-
cibus et al.29 repeated the same study in a larger
population of patients with IBD. Also in this
study, a higher frequency of variant BclI carriers
in patients with Crohn’s disease was observed.
These authors also reported that patients car-
rying the BclI polymorphism responded better
to GC treatment and were less likely to need
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms
additional courses of steroid treatment.29 In
contrast, a recent Dutch study showed a lower
frequency of the BclI polymorphism in IBD, in
particular in patients with Crohn’s disease.66
These findings, as well as the increased re-
sponsiveness to GC treatment, are in accor-
dance with increased GC effects, as may be
expected in BclI carriers. Additional research is
needed to study the exact relationship between
IBD and GR variants and elucidate these con-
flicting results. No associations were found be-
tween the BclI polymorphism and rheumatoid
arthritis in previous studies.31,67 However, re-
cent data showing a lower frequency of BclI G-
allele carriers in Dutch rheumatoid arthritis pa-
tients compared to healthy controls may point
toward a reduced risk of rheumatoid arthritis
in BclI carriers.50
Other associations concerning the BclI poly-
morphism are found in cystic fibrosis patients
and patients with skin cancer. A recently pub-
lished study by Corvol et al. showed a relation-
ship between lung disease progression and the
presence of the BclI polymorphism in cystic fi-
brosis patients, which is possibly mediated by an
altered susceptibility to inflammation.68 Con-
cerning nonmelanoma skin cancers, it has pre-
viously been reported that a higher risk of de-
veloping nonmelanoma skin cancer was found
in subjects using GC treatment.69,70 In this con-
text, Patel et al.71 investigated the effect of the
BclI polymorphism on the development of skin
cancer in patients using GCs. It was demon-
strated that carriers of this polymorphism with
prolonged use of higher doses of GCs had a
higher risk of developing squamous cell carci-
noma (SCC). They found no association be-
tween the BclI polymorphism and the risk in
developing SCC in patients who were not ex-
posed to GCs or with the development of basal
cell carcinoma.71
Recently, several studies showed associations
between the BclI polymorphism and major
depression. The BclI GG variant was more
frequent in a group of German Caucasians
with major depression.37 This finding was
confirmed in another German case–control
189
study.15 Also, in premenopausal women with
major depression, the frequency of homozy-
gous BclI carriers was found to be higher.72
In this study the female BclI GG carriers
had an increased WHR, which may result
from increased GC sensitivity. Interestingly,
Brouwer et al. found that depressive BclI car-
riers had higher ACTH levels and showed a
trend toward a worse response rate to antide-
pressant treatment.73 The associations found
between GR polymorphisms and depression
are extensively described elsewhere.74 Other
psychiatric disorders have also been shown
to be accompanied by altered HPA axis ac-
tivity, such as post-traumatic stress disorder
(PTSD).75,76 Bachmann et al. reported in a
subset of patients suffering from PTSD car-
rying the BclI GG genotype that the severity
of PTSD was greater.77 Patients with the GG
genotype also seemed to be more responsive
to GCs, as was tested with a dermal vasocon-
strictor assay, which is in line with the data
of Panarelli et al., showing an enhanced sensi-
tivity in vivo to budesonide in GG carriers of
the BclI polymorphism.63 However, in a re-
cent study by Kumsta et al.78 in healthy sub-
jects, the BclI GG genotype carriers showed
the least degree of skin blanching, suggesting
a decreased GC sensitivity of subdermal blood
vessels. In this study no association between
this GR variant and GC sensitivity of periph-
eral leukocytes was found. Thus, the effects
of the BclI polymorphism on influencing GC
sensitivity may be tissue dependent and may
also be state dependent. In addition, other fac-
tors, such as ethnicity and group sizes, may
explain differences between these mentioned
results.
At present, the exact mechanism through
which the BclI polymorphism may alter GC ef-
fects is unclear. This polymorphism is intronic
and its location does not involve a coding, reg-
ulatory or splicing part of the GR gene. It is
possible that this polymorphism is in linkage
with other variations, e.g., in the promoter re-
gion, or linked to other functionally important
polymorphisms.
190 Annals of the New York Academy of Sciences

TABLE 3. Data from Studies that Investigated the Association between the Bcl I Polymorphism of the
Glucocorticoid Receptor Gene and Clinical Parameters
Association with the
Reference Population BclI polymorphism

Bachmann et al.77 118 Vietnam war veterans with PTSD and • Association with low cortisol levels in PTSD
42 Vietnam war veterans without PTSD patients
• Increased responsiveness to dermal
vasoconstriction test and correlation with
severity of PTSD
Brouwer et al.73 98 patients with unipolar depression • Trend toward reduced response to
antidepressive therapy
• Increased ACTH levels in the DEX/CRH
test
Buemann et al.60 79 men and 73 women • Increased abdominal visceral fat in lean
homozygous carriers
• No association with overweight in
homozygous carriers
Clement et al.61 80 obese families • Trend toward obesity
• No association after replication
Corvol et al.68 255 patients with CF • Progression of lung disease in carriers
Di Blasio et al.47 185 obese women, 94 obese men • Interaction with the N363S polymorphism:
higher cholesterol levels and trend for
higher blood pressures
Krishnamurthy 53 premenopausal women with unipolar • Association with major depression
et al.72 depression and 29 controls
• Association with increased WHR in
depressive women
Kuningas et al.23 563 Dutch subjects with age > 85 years • No association with cortisol levels, CRP,
HDL- and LDL-cholesterol levels,
triglycerides, or HbA1c
Kumsta et al.78 206 healthy individuals • Reduced skin blanching after dermally
applied beclomethasone
Kumsta et al.84 206 healthy individuals • Male BclI GG carriers showed reduced
ACTH and total cortisol responses to
psychosocial stress
• Female BclI GG carriers (all using oral
contraceptives) showed highest total cortisol
responses after stress tests
Lee et al.67 149 Korean RA patients and 149 healthy • No association with RA
Korean controls
Patel et al.71 657 patients with NMSC and 393 controls • Higher risk of developing SCC in carriers
with prolonged use or higher doses of GCs
Panarelli et al.63 64 men • No association with BMI
• Increased in vivo sensitivity to budesonide in
homozygous carriers
Rosmond et al.57 284 Swedish men • Increased BMI
• Increased waist to hip circumference
• Increased abdominal sagittal diameter
• Increased leptin levels
van Rossum et al.56 197 Dutch elderly subjects, 1963 elderly • Hypersensitivity to dexamethasone
males and females, 400 elderly males • Lower BMI
• Trend toward lower lean mass
• No association with fat mass
Continued
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms 191

TABLE 3. Continued
Association with the
Reference Population BclI polymorphism

van Rossum et al.37 490 patients with major depression and • Association with major depression
496 controls
Stevens et al.91 216 U.K. Caucasians (in 116 a DST was • Increased cortisol suppression after low dose
performed) DEX
Tremblay et al.58 90 male and 83 female adolescents • Greater increase in subcutaneous fat mass
during 12 year in female heterozygous
carriers than noncarriers and homozygous
carriers
Ukkola et al.92 12 pairs of monozygotic twins • Noncarriers had greater increase in weight,
abdominal visceral fat, and cholesterol levels
in response to overfeeding
Ukkola et al.59 322 men and 420 women • Abdominal visceral fat
• Interactions with lipoprotein lipase gene and
adrenergic receptor gene
Watt et al.64 864 adults and their parents • Associations with personal and parental
hypertension
Weaver et al.62 56 obese and 43 nonobese premenopausal • Hyperinsulinemia in obese carriers
women • No association with obesity
Wüst et al.53 112 healthy men • Associations with a reduced salivary cortisol
response and a trend toward lower ACTH
levels after psychosocial stress
Zobel et al.15 322 in patients with recurrent unipolar • Association with major depression
depression and 298 controls
Abbreviations: PTSD, post-traumatic stress disorder; ACTH, adrenocorticotrophic hormone; CF; cystic fibrosis;
WHR, waist-to-hip ratio; CRP, C-reactive protein; DEX/CRH; dexamethasone/corticotrophin-releasing hormone;
HDL, high-density lipoprotein; LDL, low-density lipoprotein; HbA1c, A1c subtype of hemoglobin after glucose
binding; RA, rheumatoid arthritis; NMSC, nonmelanoma skin cancer; SCC, squamous cell carcinoma; GCs, gluco-
corticoids; BMI, body mass index.

The 9β Polymorphism GR-α isoform. It is possible that increased ex-

of the GR Gene
In an “ATTTA motif ” located in the 3 UTR
of exon 9β, an A to G substitution has been re-
ported. This “ATTTA” motif is known to desta-
bilize mRNA and decrease receptor protein
expression in vitro. The ATTTA-to-GTTTA
change appears to alter mRNA stability as well
as protein expression in vitro.79 It was suggested
that this polymorphism results in increased ex-
pression and stability of GR-β in vivo. GR-β
is produced by alternative splicing of the GR
gene. This β isoform of the GR resides in the
nucleus of cells and does not bind GCs or acti-
vate GC-response genes. It functions as a dom-
inant negative inhibitor of the active receptor
pression and stability of the GR-β variant of
the GR leads to a relative GC resistance. De-
rijk et al. demonstrated that the 9β polymor-
phism may result in increased expression and
stabilisation of the β variant of the GR, which
functions as an active inhibitor of the active
form of the GR, the GR-α variant.79 van den
Akker et al.80 studied transactivation and tran-
srepression of the 9β polymorphism ex vivo. GC-
induced upregulation of GILZ mRNA through
transactivation did not significantly differ in 9β
homozygous persons, while the downregula-
tion of interleukin-2 (IL-2) expression through
transrepression was decreased. The effects of
the GR on inflammation and the immune sys-
tem are mainly mediated by transrepression
192 Annals of the New York Academy of Sciences

TABLE 4. Data from Studies that Investigated the Associations between the 9β Polymorphism of the GR
Gene and Clinical Parameters
Association with the
Reference Population 9β polymorphism

van den Akker80 216 Dutch elderly • No association with cortisol suppression
after DST
• No associations with BMI, WHR, insulin
sensitivity, lipid profile, and CRP
van den Akker32 3851 Dutch elderly, 678 carriers of nasal S. • Lower risk of persistent S. aureus nasal
aureus, 2,804 non-carriers carriage in homozygous carriers
van den Akker82 4878 Dutch elderly aged over 55 years • Increased risk of MI and CHD in
homozygous carriers
• Higher levels of hs-CRP, IL-6, and cIMT
Donn et al.31 198 RA patients and 393 control subjects • No association with RA
DeRijk et al.79 30 RA patients, 40 SLE patients, 24 controls • Association with RA
• Increased stability of GR-β mRNA
Kumsta et al.84 206 healthy individuals • Male carriers showed increased ACTH and
total cortisol responses to psychosocial stress
• Male carriers had elevated ACTH levels
after a DST
Spijker et al.17 241 patients with bipolar disorder and 532 • Reduced risk of BD
controls • Less manic and hypomanic episodes in BD
patients
Syed et al.83 322 Europid subjects and 262 South-Asian • Lower WHR in Europid women
subjects • More favorable lipid profile in Europid men
• No association with systolic and diastolic
blood pressure, fasting glucose, and insulin
levels during OGTT
Abbreviations: ACTH, adrenocorticotrophic hormone; DST, dexamethasone suppression test; BMI, body mass
index; WHR, waist to hip ratio; hs-CRP, high sensitive C-reactive protein; S. aureus, Staphylococcus aureus; IL, interleukin;
cIMT, carotis intima media thickness; RA, rheumatoid arthritis; OGTT, oral glucose tolerance test; BD, bipolar
disorder; SLE, systemic lupus erythematosus; MI, myocardial infarction; CHD, coronary heart disease.

through direct protein–protein interactions. We Increased risk of autoimmune diseases, such

showed that transactivation is not influenced
by the 9β polymorphism, but transrepression
is significantly reduced, and thus a more ac-
tive immune system might be expected in 9β
carriers.80
Clinical measures of transrepressive GR ac-
tivity on the inflammatory and immune system
(acquired and innate) were significantly asso-
ciated with the 9β haplotype. The innate im-
mune system is thought to play an important
role in microbial colonization. In humans, the
anterior nares are the primary ecological reser-
voir of S. aureus. Persons homozygous for the 9β
haplotype had a 68% reduced risk of persistent
S. aureus nasal carriage.32
as rheumatoid arthritis, in which regulation of
the acquired immune system plays an impor-
tant role, has been found in persons carry-
ing the GR-9β polymorphism. DeRijk et al.
found an association between the 9β poly-
morphism and rheumatoid arthritis patients.79
However, Donn et al. did not find this associa-
tion.31 Both these studies did not include hap-
lotype analysis or the ER22/23EK polymor-
phism, which is linked to the 9β polymorphism.
Recently preliminary data on GR haplotype
association in a large study of patients with
rheumatoid arthritis (n = 368) compared to
controls (n = 5033) were presented. Carriers of
the 9β haplotype (without ER22/23EK) had a
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms 193

TABLE 5. Effects of the Polymorphisms in the GR Gene Discussed in this Review

In Vitro Response to
DEX
Trans- Trans- Cortisol Phenotype (for details
activation repression levels 1 mg 0.25 mg see Tables 1–4)

TthIII I Not tested Not tested ↑ = = Reduced risk of bipolar disorder,

lower volume of hippocampus
and amygdala, association with
depression
ER22/23EK ↓ = = ↓ = Healthy metabolic profile, beneficial
body composition, longevity,
decreased risk of dementia,
increased risk of depression
N363S ↑ = = = ↑ Increased BMI (in some studies),
elevated cholesterol levels
BclI Not tested Not tested = ↑ ↑ More (abdominal) body fat, less lean
mass, increased risk of depression
9β = ↓ = = =/↓ Increased risk of myocardial
infarction, higher hs-CRP levels,
lower risk in S. aureus nasal
carriage, beneficial body
composition, increased risk of
autoimmune diseases, e.g., RA,
IBD
Abbreviations: DEX, dexamethasone; BMI, body mass index; hs-CRP, high sensitivity C-reactive protein; S. aureus,
Staphylococcus aureus; RA, rheumatoid arthritis; IBD, inflammatory bowel disease. ↓, decrease; ↑, increase; =, no
difference.

higher risk of rheumatoid arthritis compared to
controls.50
The presence of a more active immune status
in persons carrying the 9β haplotype is further
supported by our finding of elevated levels of
inflammatory parameters like IL-6 and CRP
levels measured with high sensitivity (hs-CRP)
in a general elderly population. Thus, persons
carrying the 9β haplotype seem to have a subtle
but chronic pro-inflammatory status. In recent
years, inflammation has been demonstrated to
be one of the key players in the process of
atherosclerosis.81 Therefore, the incidence of
myocardial infarction (MI) and coronary heart
disease (CHD) in relation to the 9β polymor-
phism was studied in a large Dutch population-
based study. In this study, CHD was defined as
MI, percutaneous transluminal coronary an-
gioplasty, coronary artery bypass graft, and
death from CHD. In this study in Dutch el-
derly persons, persons homozygous for the 9β
haplotype had increased intima media thick-
ness and an almost threefold increased risk of
cardiovascular disease.82
To investigate the effect of the 9β polymor-
phism on GC sensitivity, a DST in 187 Dutch
persons aged over 55 years was performed. No
significant differences were found between car-
riers and noncarriers of the 9β polymorphism
concerning DST, BMI, WHR, insulin sensi-
tivity, total cholesterol, LDL-cholesterol, and
HDL-cholesterol concentrations.80
However, Syed et al. found an association be-
tween the 9β polymorphism and a more fa-
vorable lipid profile in men and a decreased
WHR in women.83 These are interesting find-
ings, since a reduced GC effect (with respect
to transactivation of certain target genes) could
be expected to result in these clinical features.
Remarkably, Kumsta et al. recently showed
194
associations of this GR variant with increased
ACTH and total cortisol responses to psychoso-
cial stress (Trier Social Stress Test) and in reac-
tion to the administration of a low dose DST in
males, which may reflect diminished HPA axis
feedback sensitivity at the pituitary level.84
Another association that was found concern-
ing the 9β polymorphism is a trend toward a
lower frequency of the 9β polymorphism in
bipolar disorder patients compared to healthy
controls. In addition, the frequency of this poly-
morphism was higher in the group of patients
with fewer (hypo-) manic episodes. This sug-
gests a protective effect of the 9β polymor-
phism.17
Table 4 summarizes those studies addressing
the effects of the 9β polymorphism on corti-
sol sensitivity, obesity, lipid profile, insulin resis-
tance, and the immune system. These results
suggest that the 9β polymorphism has an im-
portant role in immune cells, and the effect of
the 9β polymorphism could be limited to tissues
with high levels of the β variant of the GR.80
High levels of the GR-β isoform are found in
immune cells.85 In other cells, the β variant was
not found, and therefore the effect of the 9β
polymorphism on other tissues and cells than
immune cells could be limited.
Conclusions
Some polymorphisms of the GR gene have
been shown to subtly alter the effects of GCs
at the tissue level. In intervention studies in
the normal, healthy population, using DSTs, a
broad range of sensitivity to the exogenous GC
dexamethasone has been demonstrated.86 The
many reported alterations in GC-affected tis-
sues and GC regulated processes (e.g., changes
in lipid, glucose and fat metabolism, body com-
position, immune system, and affective and
cognitive functions) associated with GR poly-
morphisms indicate that these gene variants
may also influence cortisol effects intracellu-
larly by modification of the GR. Table 5 sum-
marizes the effects of GR polymorphisms on
Annals of the New York Academy of Sciences
GR action in vitro, as well as the correspond-
ing cortisol levels and results of the DST in
vivo. Previous studies often focused on the re-
lationship of serum cortisol levels and several
types of disease. However, in many studies this
yielded conflicting data. It is likely that serum
cortisol concentrations poorly reflect cortisol
sensitivity and the subsequent biological cor-
tisol effects at the tissue level. Since several GR
gene polymorphisms have been shown to be re-
lated to altered GC sensitivity, they may serve as
markers of GC sensitivity. However, additional
factors (e.g., 11ß-HSD and P-glycoprotein ac-
tivity, and mineralocorticoid receptor function-
ing) can also affect GC sensitivity and should
also be taken into account. Importantly, repli-
cation of many of the clinical associations with
GR variants found so far is needed to confirm
the reported data. Discrepancies between ob-
served associations may be partially explained
by tissue-specific factors and state-dependent
variables, which influence the expression of the
different splice variants and translational vari-
ants of the GR, as well as post-translational
modification of this receptor.87
The exact underlying mechanisms by which
these polymorphisms modify GC action re-
main to be unraveled. For the ER22/23EK and
the 9β variant there seems to be a mechanis-
tic explanation. However, for BclI and N363S,
the mechanism is unknown. Future research
may provide further information on the effects
of GR polymorphisms and translation of the
findings to clinical practice.
Conflicts of Interest
The authors declare no conflicts of interest.
References
1. Antoni, F.A. 1986. Hypothalamic control of adreno-
corticotropin secretion: advances since the discovery
of 41-residue corticotropin-releasing factor. Endocr.
Rev. 7: 351–378.
2. Chrousos, G.P. 1992. Regulation and dysregula-
tion of the hypothalamic-pituitary-adrenal axis. The
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms
corticotropin-releasing hormone perspective. En-
docrinol. Metab. Clin. North Am. 21: 833–858.
3. Lundblad, J.R. & J.L. Roberts. 1988. Regulation of
proopiomelanocortin gene expression in pituitary.
Endocr. Rev. 9: 135–158.
4. Beyer, H.S., S.G. Matta & B.M. Sharp. 1988.
Regulation of the messenger ribonucleic acid for
corticotropin-releasing factor in the paraventricular
nucleus and other brain sites of the rat. Endocrinology
123: 2117–2123.
5. Huizenga, N.A. et al. 1998. Interperson variability
but intraperson stability of baseline plasma cortisol
concentrations, and its relation to feedback sensitivity
of the hypothalamo-pituitary-adrenal axis to a low
dose of dexamethasone in elderly individuals. J. Clin.
Endocrinol. Metab. 83: 47–54.
6. Monder, C. & P.C. White. 1993. 11 beta-
hydroxysteroid dehydrogenase. Vitam. Horm. 47:
187–271.
7. Stewart, P.M. & Z.S. Krozowski. 1999. 11 beta-
hydroxysteroid dehydrogenase. Vitam. Horm. 57:
249–324.
8. Encio, I.J. & S.D. Detera-Wadleigh. 1991. The ge-
nomic structure of the human glucocorticoid recep-
tor. J. Biol. Chem. 266: 7182–7188.
9. Schaaf, M.J. & J.A. Cidlowski. 2003. Molecular deter-
minants of glucocorticoid receptor mobility in living
cells: the importance of ligand affinity. Mol. Cell. Biol.
23: 1922–1934.
10. Stahn, C. et al. 2007. Molecular mechanisms of gluco-
corticoid action and selective glucocorticoid receptor
agonists. Mol. Cell Endocrinol. 275: 71–78.
11. Perretti, M. & A. Ahluwalia. 2000. The microcircu-
lation and inflammation: site of action for glucocor-
ticoids. Microcirculation 7: 147–161.
12. Charmandari, E. et al. 2008. Generalized glucocor-
ticoid resistance: clinical aspects, molecular mecha-
nisms, and implications of a rare genetic disorder. J.
Clin. Endocrinol. Metab. 93: 1563–1572.
13. Rosmond, R. et al. 2000. A polymorphism of the 5’-
flanking region of the glucocorticoid receptor gene lo-
cus is associated with basal cortisol secretion in men.
Metabolism 49: 1197–1199.
14. van Rossum, E.F. et al. 2004. Characterization of
a promoter polymorphism in the glucocorticoid
receptor gene and its relationship to three other
polymorphisms. Clin. Endocrinol. (Oxf.) 61: 573–
581.
15. Zobel, A. et al. 2008. Unipolar depression and hip-
pocampal volume: impact of DNA sequence variants
of the glucocorticoid receptor gene. Am. J. Med. Genet.
B. Neuropsychiatr. Genet. 147: 836–843.
16. Hasler, G. et al. 2004. Discovering endopheno-
types for major depression. Neuropsychopharmacology
29: 1765–1781.
195
17. Spijker, A.T. et al. 2009. Functional polymorphism
of the glucocorticoid receptor gene associates with
mania and hypomania in bipolar disorder. Bipolar
Disord. 11: 95–101.
18. Koper, J.W. et al. 1997. Lack of association between
five polymorphisms in the human glucocorticoid re-
ceptor gene and glucocorticoid resistance. Hum. Genet.
99: 663–668.
19. van Rossum, E.F. et al. 2002. A polymorphism in the
glucocorticoid receptor gene, which decreases sen-
sitivity to glucocorticoids in vivo, is associated with
low insulin and cholesterol levels. Diabetes 51: 3128–
3134.
20. Russcher, H. et al. 2005. Two polymorphisms in
the glucocorticoid receptor gene directly affect
glucocorticoid-regulated gene expression. J. Clin. En-
docrinol. Metab. 90: 5804–5810.
21. Koeijvoets, K.C. et al. 2006. A functional polymor-
phism in the glucocorticoid receptor gene and its re-
lation to cardiovascular disease risk in familial hyper-
cholesterolemia. J. Clin. Endocrinol. Metab. 91: 4131–
4136.
22. van Rossum, E.F. et al. 2004. Association of the
ER22/23EK polymorphism in the glucocorticoid
receptor gene with survival and C-reactive pro-
tein levels in elderly men. Am. J. Med. 117: 158–
162.
23. Kuningas, M. et al. 2006. Genetic variants in the glu-
cocorticoid receptor gene (NR3C1) and cardiovascu-
lar disease risk. The Leiden 85-plus Study. Biogeron-
tology 7: 231–238.
24. van Rossum, E.F. et al. 2004. The ER22/23EK poly-
morphism in the glucocorticoid receptor gene is asso-
ciated with a beneficial body composition and muscle
strength in young adults. J. Clin. Endocrinol. Metab. 89:
4004–4009.
25. Finken, M.J. et al. 2007. The 23K variant of the
R23K polymorphism in the glucocorticoid receptor
gene protects against postnatal growth failure and in-
sulin resistance after preterm birth. J. Clin. Endocrinol.
Metab. 92: 4777–4782.
26. Chrousos, G.P. 1995. The hypothalamic-pituitary-
adrenal axis and immune-mediated inflammation.
N. Engl. J. Med. 332: 1351–1362.
27. van Winsen, L.M. et al. 2007. Glucocorticoid recep-
tor gene polymorphisms associated with more ag-
gressive disease phenotype in MS. J. Neuroimmunol.
186: 150–155.
28. Boyle, B. et al. 2008. Polymorphisms of the glucocor-
ticoid receptor gene in Graves ophthalmopathy. Br. J.
Ophthalmol. 92: 131–134.
29. De Iudicibus, S. et al. 2007. Association of BclI poly-
morphism of the glucocorticoid receptor gene lo-
cus with response to glucocorticoids in inflammatory
bowel disease. Gut 56: 1319–1320.
196
30. Decorti, G. et al. 2006. Glucocorticoid receptor poly-
morphisms in inflammatory bowel disease. Gut 55:
1053–1054.
31. Donn, R., D. Payne & D. Ray. 2007. Glucocorticoid
receptor gene polymorphisms and susceptibility to
rheumatoid arthritis. Clin. Endocrinol. (Oxf.) 67: 342–
345.
32. van den Akker, E.L. et al. 2006. Staphylococcus au-
reus nasal carriage is associated with glucocorticoid
receptor gene polymorphisms. J. Infect. Dis. 194: 814–
818.
33. Kalmijn, S. et al. 1998. A prospective study on cor-
tisol, dehydroepiandrosterone sulfate, and cognitive
function in the elderly. J. Clin. Endocrinol. Metab. 83:
3487–3492.
34. Rasmuson, S. et al. 2001. Increased glucocorticoid
production and altered cortisol metabolism in women
with mild to moderate Alzheimer’s disease. Biol. Psy-
chiatry 49: 547–552.
35. Seeman, T.E. et al. 1997. Increase in urinary corti-
sol excretion and memory declines: MacArthur stud-
ies of successful aging. J. Clin. Endocrinol. Metab. 82:
2458–2465.
36. van Rossum, E.F. et al. 2008. Glucocorticoid receptor
variant and risk of dementia and white matter lesions.
Neurobiol. Aging 29: 716–723.
37. van Rossum, E.F. et al. 2006. Polymorphisms of the
glucocorticoid receptor gene and major depression.
Biol. Psychiatry 59: 681–688.
38. van West, D. et al. 2006. Glucocorticoid receptor
gene-based SNP analysis in patients with recurrent
major depression. Neuropsychopharmacology 31: 620–
627.
39. Russcher, H. et al. 2005. Increased expression of the
glucocorticoid receptor-A translational isoform as a
result of the ER22/23EK polymorphism. Mol. En-
docrinol. 19: 1687–1696.
40. Yudt, M.R. & J.A. Cidlowski. 2001. Molecular identi-
fication and characterization of a and b forms of the
glucocorticoid receptor. Mol. Endocrinol. 15: 1093–
1103.
41. Huizenga, N.A. et al. 1998. A polymorphism in the
glucocorticoid receptor gene may be associated with
and increased sensitivity to glucocorticoids in vivo. J.
Clin. Endocrinol. Metab. 83: 144–151.
42. Lin, R.C., W.Y. Wang & B.J. Morris. 1999. High
penetrance, overweight, and glucocorticoid recep-
tor variant: case-control study. BMJ 319: 1337–
1338.
43. Dobson, M.G. et al. 2001. The N363S polymorphism
of the glucocorticoid receptor: potential contribution
to central obesity in men and lack of association with
other risk factors for coronary heart disease and di-
abetes mellitus. J. Clin. Endocrinol. Metab. 86: 2270–
2274.
Annals of the New York Academy of Sciences
44. Halsall, D.J. et al. 2000. Glucocorticoid receptor vari-
ant and body mass index. Rapid Response to Br. Med.
J. 7221: 1337–1338.
45. Echwald, S.M. et al. 2001. The Asn363Ser variant
of the glucocorticoid receptor gene is not associated
with obesity or weight gain in Danish men. Int. J.
Obes. Relat. Metab. Disord. 25: 1563–1565.
46. Rosmond, R., C. Bouchard & P. Bjorntorp. 2001.
Tsp509I polymorphism in exon 2 of the glucocorti-
coid receptor gene in relation to obesity and cortisol
secretion: cohort study. BMJ 322: 652–653.
47. Di Blasio, A.M. et al. 2003. The relation between two
polymorphisms in the glucocorticoid receptor gene
and body mass index, blood pressure and cholesterol
in obese patients. Clin. Endocrinol. (Oxf.) 59: 68–74.
48. Buemann, B. et al. 2005. The N363S polymorphism
of the glucocorticoid receptor and metabolic syn-
drome factors in men. Obes. Res. 13: 862–867.
49. Marti, A. et al. 2006. Meta-analysis on the effect of the
N363S polymorphism of the glucocorticoid receptor
gene (GRL) on human obesity. BMC Med. Genet. 7:
50.
50. van Oosten, M.J.M. et al. Polymorphisms in the
glucocorticoid receptor gene which modulate glu-
cocorticoid sensitivity are associated with rheuma-
toid arthritis. Abstract Annual European Congress
of Rheumatology (EULAR), Barcelona 2007.
51. Bonifati, D.M. et al. 2006. The glucocorticoid re-
ceptor N363S polymorphism and steroid response
in Duchenne dystrophy. J. Neurol. Neurosurg. Psychiatry
77: 1177–1179.
52. Luczay, A. et al. 2006. Potential advantage of
N363S glucocorticoid receptor polymorphism in 21-
hydroxylase deficiency. Eur. J. Endocrinol. 154: 859–
864.
53. Wüst, S. et al. 2004. Common polymorphisms in
the glucocorticoid receptor gene are associated with
adrenocortical responses to psychosocial stress. J.
Clin. Endocrinol. Metab. 89: 565–573.
54. Jewell, C.M. & J.A. Cidlowski. 2007. Molecular ev-
idence for a link between the N363S glucocorticoid
receptor polymorphism and altered gene expression.
J. Clin. Endocrinol. Metab. 92: 3268–3277.
55. Murray, J.C. et al. 1987. RFLP for the glucocorticoid
receptor (GRL) located at 5q11–5q13. Nucleic Acids
Res. 15: 6765.
56. van Rossum, E.F. et al. 2003. Identification of the BclI
polymorphism in the glucocorticoid receptor gene:
association with sensitivity to glucocorticoids in vivo
and body mass index. Clin. Endocrinol. (Oxf.) 59: 585–
592.
57. Rosmond, R. et al. 2000. A glucocorticoid recep-
tor gene marker is associated with abdominal obe-
sity, leptin, and dysregulation of the hypothalamic-
pituitary-adrenal axis. Obes. Res. 8: 211–218.
Manenschijn et al.: Glucocorticoid Receptor Polymorphisms
58. Tremblay, A. et al. 2003. Long-term adiposity
changes are related to a glucocorticoid receptor poly-
morphism in young females. J. Clin. Endocrinol. Metab.
88: 3141–3145.
59. Ukkola, O. et al. 2001. Interactions among the glu-
cocorticoid receptor, lipoprotein lipase and adrener-
gic receptor genes and abdominal fat in the Quebec
Family Study. Int. J. Obes. Relat. Metab. Disord. 25:
1332–1339.
60. Buemann, B. et al. 1997. Abdominal visceral fat is
associated with a BclI restriction fragment length
polymorphism at the glucocorticoid receptor gene
locus. Obes. Res. 5: 186–192.
61. Clement, K. et al. 1996. Candidate gene approach
of familial morbid obesity: linkage analysis of the
glucocorticoid receptor gene. Int. J. Obes. Relat. Metab.
Disord. 20: 507–512.
62. Weaver, J.U., G.A. Hitman & P.G. Kopelman. 1992.
An association between a Bc1I restriction fragment
length polymorphism of the glucocorticoid receptor
locus and hyperinsulinaemia in obese women. J. Mol.
Endocrinol. 9: 295–300.
63. Panarelli, M. et al. 1998. Glucocorticoid recep-
tor polymorphism, skin vasoconstriction, and other
metabolic intermediate phenotypes in normal hu-
man subjects. J. Clin. Endocrinol. Metab. 83: 1846–
1852.
64. Watt, G.C. et al. 1992. Abnormalities of glucocorti-
coid metabolism and the renin-angiotensin system:
a four-corners approach to the identification of ge-
netic determinants of blood pressure. J. Hypertens. 10:
473–482.
65. Werner, S.C. 1977. Modification of the classification
of the eye changes of Graves’ disease: recommen-
dations of the Ad Hoc Committee of the American
Thyroid Association. J. Clin. Endocrinol. Metab. 44:
203–204.
66. van Oosten, M.J.M. et al. The glucocorticoid recep-
tor gene polymorphism BclI which modulates gluco-
corticoid sensitivity is associated with inflammatory
bowel disease. Abstract from Annual Meeting of the
Endocrine Society 2008.
67. Lee, E.B. et al. 2005. Glucocorticoid receptor poly-
morphisms in Korean patients with rheumatoid
arthritis. Ann. Rheum. Dis. 64: 503–504.
68. Corvol, H. et al. 2007. Glucocorticoid receptor gene
polymorphisms associated with progression of lung
disease in young patients with cystic fibrosis. Respir.
Res. 8: 88.
69. Karagas, M.R. et al. 1999. Increase in incidence
rates of basal cell and squamous cell skin cancer in
New Hampshire, USA. New Hampshire Skin Can-
cer Study Group. Int. J. Cancer 81: 555–559.
70. Sorensen, H.T. et al. 2004. Skin cancers and non-
hodgkin lymphoma among users of systemic gluco-
197
corticoids: a population-based cohort study. J. Natl.
Cancer Inst. 96: 709–711.
71. Patel, A.S. et al. 2007. Gene-drug interaction at
the glucocorticoid receptor increases risk of squa-
mous cell skin cancer. J. Invest. Dermatol. 127: 1868–
1870.
72. Krishnamurthy, P. et al. 2008. Glucocorticoid recep-
tor gene polymorphisms in premenopausal women
with major depression. Horm. Metab. Res. 40: 194–
198.
73. Brouwer, J.P. et al. 2006. Prediction of treatment
response by HPA-axis and glucocorticoid receptor
polymorphisms in major depression. Psychoneuroen-
docrinology 31: 1154–1163.
74. Spijker, A.T. & E.F.C. van Rossum. 2009. Glucocor-
ticoid receptor polymorphisms in major depression:
focus on glucocorticoid sensitivity and neurocogni-
tive functioning. Ann. N. Y. Acad. Sci. Glucocorticoids
and Mood: Clinical Manifestations, Risk Factors, and
Molecular Mechanisms. In press.
75. Meewisse, M.L. et al. 2007. Cortisol and post-
traumatic stress disorder in adults: systematic review
and meta-analysis. Br. J. Psychiatry 191: 387–392.
76. Strohle, A. et al. 2008. Blunted ACTH response
to dexamethasone suppression-CRH stimulation in
posttraumatic stress disorder. J. Psychiatr. Res. 42:
1185–1188.
77. Bachmann, A.W. et al. 2005. Glucocorticoid receptor
polymorphisms and post-traumatic stress disorder.
Psychoneuroendocrinology 30: 297–306.
78. Kumsta, R. et al. 2008. Glucocorticoid receptor gene
polymorphisms and glucocorticoid sensitivity of sub-
dermal blood vessels and leukocytes. Biol. Psychol. 79:
179–184.
79. DeRijk, R.H. et al. 2001. A human glucocorticoid
receptor gene variant that increases the stability of
the glucocorticoid receptor beta-isoform mRNA is
associated with rheumatoid arthritis. J. Rheumatol. 28:
2383–2388.
80. van den Akker, E.L. et al. 2006. Glucocorticoid re-
ceptor polymorphism affects transrepression but not
transactivation. J. Clin. Endocrinol. Metab. 91: 2800–
2803.
81. Libby, P. 2002. Inflammation in atherosclerosis. Na-
ture 420: 868–874.
82. van den Akker, E.L. et al. 2008. Glucocorticoid re-
ceptor gene and risk of cardiovascular disease. Arch.
Intern. Med. 168: 33–39.
83. Syed, A.A. et al. 2006. Association of glucocorticoid
receptor polymorphism A3669G in exon 9beta with
reduced central adiposity in women. Obesity (Silver
Spring) 14: 759–764.
84. Kumsta, R. et al. 2007. Sex specific associa-
tions between common glucocorticoid receptor gene
variants and hypothalamus-pituitary-adrenal axis
198
responses to psychosocial stress. Biol. Psychiatry 62:
863–869.
85. Pujols, L. et al. 2002. Expression of glucocorticoid
receptor alpha- and beta-isoforms in human cells and
tissues. Am. J. Physiol. Cell Physiol. 283: C1324–1331.
86. van Rossum, E.F. & S.W. Lamberts. 2004. Polymor-
phisms in the glucocorticoid receptor gene and their
associations with metabolic parameters and body
composition. Recent Prog. Horm. Res. 59: 333–357.
87. Lu, N.Z. & J.A. Cidlowski. 2006. Glucocorticoid
receptor isoforms generate transcription specificity.
Trends Cell Biol. 16: 301–307.
88. Lin, R.C., X.L. Wang & B.J. Morris. 2003. Associ-
ation of coronary artery disease with glucocorticoid
receptor N363S variant. Hypertension 41: 404–407.
Annals of the New York Academy of Sciences
89. Lin, R.C. et al. 2003. Association of obesity, but not
diabetes or hypertension, with glucocorticoid recep-
tor N363S variant. Obes. Res. 11: 802–808.
90. Roussel, R. et al. 2003. The N363S polymorphism
in the glucocorticoid receptor gene is associated with
overweight in subjects with type 2 diabetes mellitus.
Clin. Endocrinol. (Oxf.) 59: 237–241.
91. Stevens, A. et al. 2004. Glucocorticoid sensitivity
is determined by a specific glucocorticoid recep-
tor haplotype. J. Clin. Endocrinol. Metab. 89: 892–
897.
92. Ukkola, O. et al. 2001. Glucocorticoid receptor Bcl
I variant is associated with an increased athero-
genic profile in response to long-term overfeeding.
Atherosclerosis 157: 221–224.