http://repub.eur.nl/res/aut/254/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/40073/ 2013-06-01T00:00:00Z Context Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive weight-adapted standard glucocorticoid replacement therapy. Clinically, some patients appear more sensitive to therapeutic administration of glucocorticoids than others. Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR) and might influence bone mineral density (BMD). Objectives To determine if bone turnover markers and BMD are associated with the GR gene polymorphism BclI in patients with PAI and CAH. Design and Patients A prospective, cross-sectional study including 74 PAI and 38 CAH patients. BMD was evaluated by DXA. Serum levels of bone turnover markers, minerals, vitamins and hormones, and urinary crosslinks were measured. Results Patients carrying the homozygous BclI polymorphism (GG) had significantly higher serum β-CrossLaps (0·37 ± 0·34 μg/l; P < 0·05) and urinary collagen crosslinks (NTX, 68·1 ± 32·4 nmol/g; P < 0·005) despite receiving the lowest average daily hydrocortisone dose of 9·9 ± 3·7 mg/m2(P < 0·05). The GG genotype occurred significantly more frequently in patients with increased NTX (OR=6·7, 95% CI = 1·78-25·38) than in patients with normal NTX. However, BMD was not significantly different between different allelic variants. No significant differences in associations of the genotypes with outcomes (or in clinical characteristics) were found between the sexes. Conclusions Although the sample sizes were relatively small and the results should be interpreted with caution, this study suggests that the homozygous (GG) genotype may be associated with higher bone resorption in adult PAI and CAH patients. GG-carriers needed a lower hydrocortisone dose on average supporting the concept that this GR variant is associated with increased cortisol sensitivity. http://repub.eur.nl/res/pub/39564/ 2013-03-01T00:00:00Z Context: The Bc/I polymorphism in the glucocorticoid receptor (GR) gene is associated with enhanced glucocorticoid (GC) sensitivity. Objective: Our objective was to investigate the association of the Bc/I polymorphism with body fatness and insulin resistance. Design and Setting: We conducted an observational cohort study, combining data from 2 cohort studies enriched with individuals with impaired glucose metabolism and/or diabetes mellitus type 2 (DM2). Patients and Methods: We examined 1228 participants (mean age 64.7 years, 45% women) from the Cohort Study on Diabetes and Atherosclerosis Maastricht (CODAM, n = 543) and the Hoorn Study (n=685). Body mass index (BMI), waist and hip circumferences, and waist-to-hip ratio (WHR) were obtained; insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA2-IR). Results: We identified 519 noncarriers (CC), 540 heterozygous (CG) carriers, and 169 homozygous (GG) carriers of the G-allele of the Bc/I polymorphism. Homozygous carriers had a higher BMI (28.9 vs 27.9 kg/m2) and waist (99.6 vs 97.2 cm) and hip (105.5 vs 103.2 cm) circumference compared with noncarriers, also after adjustment for age, sex, cohort, glucose tolerance, and lifestyle risk factors: β = 0.94 kg/m2(95% confidence interval, 0.24-1.63), β = 2.84 cm (0.95;4.73) and β = 2.38 cm (0.88-3.87), respectively. Similar results were obtained when comparing homozygous carriers with heterozygous carriers: β = 1.03 kg/m2(0.34-1.72), β = 2.20 cm (0.31-4.08) and β = 1.99 cm (0.51-3.48), respectively. There were no differences in WHR. Ln-HOMA2-IR was higher in GG carriers compared with CG carriers; 0.29 vs 0.17 [β = 0.09 (0.01-0.17)], but this effect was attenuated after adjustment for BMI [β = 0.04 (-0.04 to 0.11)]. Conclusion: Homozygous carriers of the Bc/I polymorphism of the GR gene have significantly greater total body fatness, contributing to higher HOMA2-IR, compared with heterozygous carriers and noncarriers. Copyright http://repub.eur.nl/res/pub/33236/ 2011-11-01T00:00:00Z Background: The incidence of obesity and other features of the metabolic syndrome is increased in shift workers. This may be due to a misalignment between the internal circadian rhythm and the behavioral rhythm. The stress hormone cortisol could play a role in this phenomenon because it is secreted in a circadian rhythm, and long-term elevated cortisol leads to components of the metabolic syndrome. We compared cortisol levels in scalp hair of shift and day workers to study changes in long-term cortisol due to shift work. Methods: Hair samples were collected from 33 shift workers and 89 day workers. Cortisol was extracted from the hair samples with methanol, and cortisol levels were measured using ELISA. Height and weight were measured, and body mass index (BMI) was calculated. Results: Shift workers had higher hair cortisol levels than day workers: 47.32 pg/mg hair [95% confidence interval (CI) = 38.37-58.21] vs. 29.72 pg/mg hair (95% CI = 26.18-33.73) (P < 0.001). When divided in age groups based on the median age, elevated cortisol levels were present only in younger shift workers: 48.53 pg/mg hair (95% CI = 36.56-64.29) vs. 26.42 pg/mg hair (95% CI =22.91-30.55) (P < 0.001). BMI was increased in younger shift workers as well: 27.2 (95% CI =25.5-28.8) vs. 23.7 (95% CI = 22.8-24.7) in young day workers (P = 0.001). Hair cortisol and BMI were positively correlated (β = 0.262; P = 0.005). Conclusion: Shift work at a young adultage is associated with elevated long-term cortisol levelsand increased BMI. Elevated cortisol levels and BMI may contribute to the increased cardiovascular risk found in shift workers. Copyright http://repub.eur.nl/res/pub/33816/ 2011-11-01T00:00:00Z Introduction: The hypothalamus-pituitary-adrenal (HPA)-axis is often found to be dysregulated in bipolar disorder (BD) while stress and changes in day-night rhythms can trigger a new mood episode. Genetic variants of the glucocorticoid receptor (GR)- and mineralocorticoid receptor (MR)-gene influence both the reactivity of the stress-response and associate with changes in mood. In this study we tested the hypothesis that these polymorphisms associate with different clinical characteristics of BD. Methods: We studied 326 outpatients with BD and performed GR genotyping of the TthIIII, ER22/23EK, N363S, BclI, and 9β polymorphisms, as well as MR genotyping of the 2G/C and I180V variants. All patients were interviewed for clinical characteristics. Results: Seasonal patterns of hypomania are related to the BclI haplotype and the T. thIIII. +. 9β haplotype of the GR gene (respectively, crude p= .007 and crude p= .005). Carriers of the ER22/23EK polymorphism had an almost 8 years earlier onset of their first (hypo)manic episode than non-carriers (crude p= .004, after adjustment p= .016). No evidence for a role of the MR in modifying clinical manifestations was found. Conclusion: Polymorphisms of the GR-gene are factors which influence some clinical manifestations of BD, with respect to seasonal pattern of (hypo)mania and age of onset. http://repub.eur.nl/res/pub/31458/ 2011-09-01T00:00:00Z Introduction: Elevated levels of cortisol are known to induce various symptoms and diseases, e.g. abdominal obesity, type 2 diabetes, osteoporosis and cardiovascular disease. Measuring serum, saliva and urine cortisol is limited to one time point. Measurement of cortisol in scalp hair is a recently developed method to measure long term cortisol levels. The aim of this study was to investigate whether hair cortisol is a feasible parameter to measure cortisol exposure. Experimental: We collected hair samples of 195 healthy individuals, 9 hypercortisolemic and one hypocortisolemic patient and measured hair cortisol levels. Cortisol was extracted from scalp hair using methanol and cortisol levels were measured using a salivary ELISA kit. Measurement of waist and hip circumferences and blood pressure was performed in 46 healthy subjects. Results: We found a positive correlation between hair cortisol and both waist circumference (r = 0.392, p = 0.007) and waist-to-hip ratio (WHR) (r = 0.425, p = 0.003). No correlations were found between hair cortisol levels and BMI, blood pressure or age. There was no decline in cortisol levels in six consecutive hair segments. Hair cortisol levels were elevated in patients with known hypercortisolism (p < 0.0001). Conclusions: Hair cortisol was positively correlated with WHR, suggesting that hair cortisol reflects cortisol exposure at tissue level, which was also supported by elevated hair cortisol levels in hypercortisolemic patients and concordance between hair cortisol levels and clinical disease course. Cortisol levels in hair are slightly influenced by hair treatment but not by natural hair colour, use of hair products, gender or age. http://repub.eur.nl/res/pub/34070/ 2011-05-16T00:00:00Z Staphylococcus aureus (S. aureus) colonizes the anterior nares in part of the population and the persistent carrier state is associated with increased infection risk. Knowledge concerning the determinants of S. aureus nasal carriage is limited. Previously, we found that glucocorticoid receptor polymorphisms influence carrier risk, suggesting involvement of glucocorticoids. Our aim was to study long-term cortisol levels in non-carriers, intermittent, and persistent carriers of S. aureus. We hypothesized that cortisol levels are higher in carriers, since cortisol-induced immune suppression would enhance S. aureus colonization. We determined nasal carrier state and long-term hair cortisol levels in 72 healthy subjects. Nasal swabs were collected twice with an interval of 2 weeks. Cortisol levels were determined in hair segments of 3 cm, which corresponds to a period of roughly 3 months. Of all 72 participants, 38 were non-carriers, 10 were intermittent carriers, and 24 were persistent carriers of S. aureus. Cortisol levels did not differ between these carrier groups (p = 0.638). Long-term cortisol levels are not associated with S. aureus nasal carriage. http://repub.eur.nl/res/pub/34517/ 2011-04-01T00:00:00Z Delirium is the most common mental disorder at older age in hospitals after acute admission. The pathogenesis of delirium is largely unknown. Hyperactivity of the hypothalamic-pituitary-adrenal axis, leading to increased cortisol levels, has been suggested to play a role in the development of delirium. The effects of cortisol, the most important glucocorticoid (GC) in humans, are mainly mediated by the GC receptor (GR). Several polymorphisms in the GR gene that alter the GC sensitivity are known. The aim of this study was to study the role of these GR polymorphisms in delirium in elderly patients. Patients aged 65 years and older admitted to the medical department or scheduled for hip surgery were included. Delirium was diagnosed using the Confusion Assessment Method. Five single nucleotide polymorphisms in the GC receptor gene were genotyped and haplotypes were constructed. Delirium was associated with impaired cognitive (P < 0.001) and functional function (P < 0.001), as well as with older age (P < 0.001). Homozygous carriers of haplotype 4, characterized by the presence of the BclI and TthIIII minor alleles, had a 92% decreased risk of developing delirium (P = 0.02), independent of age, cognitive, and functional state. Homozygous carriage of the BclI-TthIIII haplotype of the GR gene is related to a reduced risk of developing delirium. This suggests that altered GC signaling may be involved in the pathogenesis and development of delirium in the elderly. http://repub.eur.nl/res/pub/28082/ 2010-12-01T00:00:00Z Objective: Smaller size at birth has been associated with an increased risk of metabolic and cardiovascular disorders in adult life. Fetal programing of the hypothalamic - pituitary - adrenal axis has been suggested as a possible explanation. Fetal glucocorticoid (GC) overexposure has effects that suggest a role of GCs in this programing. The effects of GCs are mediated through the GC receptor (GR or NR3C1). Several functional polymorphisms have been described, which are associated with relative GC resistance or hypersensitivity. Our aim is to compare frequencies of GR haplotypes, characterized by the R23K, N363S, Bcl1, or 9β polymorphisms, in subjects born small for gestational age (SGA) and associate birth anthropometry data, response to GH treatment, blood pressure, glucose and insulin concentrations, and body composition with these haplotypes. Design: In total, 418 SGA subjects and 697 healthy controls were enrolled in this study. Methods: Anthropometry data were obtained, as well as blood samples to determine fasting glucose and insulin concentrations. Dual energy X-ray absorptiometry scans were used to measure the amount of fat and lean mass. Results: No differences were found between GR haplotype frequencies in SGA children compared with healthy controls. No associations were found between GR haplotypes and birth length and birth weight, growth response during GH treatment, blood pressure, glucose and insulin concentrations, and body composition. Conclusion: GR haplotypes and their effect on GC sensitivity do not seem to play a significant role in GH-induced catch-up growth and the risk factors of developing metabolic and cardiovascular disorders in adult life of SGA children. http://repub.eur.nl/res/pub/31738/ 2010-12-01T00:00:00Z Changes in glucocorticoid (GC) receptor sensitivity can be categorized in three different types. First, generalized GC resistance syndrome is a hereditary disease. Patients present with signs and symptoms of increased androgen and/or mineralocorticoid action, combined with biochemical hypercortisolism, but lack of cushingoid features. Second, at a tissue level, transient changes in GC sensitivity are present during disease. Transient changes in GC sensitivity of leukocytes during infectious diseases like sepsis have been found, but also acquired forms or GC resistance occur, in particular in some types of neoplasms, major depression, AIDS, and several autoimmune diseases. Third, at the level of the general population, the diversity in GC sensitivity has a wide interindividual variation which in part can be explained by genetic variation of the GC receptor gene. Several single nucleotide polymorphisms of the gene have been associated with changes in GC sensitivity and its clinical phenotype. In this chapter, four genetic variants are described of which two (rs6198 and rs6189/6190) are associated with a relative GC resistance and two (rs1695 and rs41423247) are associated with a relative GC hypersensitivity. Copyright http://repub.eur.nl/res/pub/28486/ 2010-08-21T00:00:00Z Introduction: The glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9β are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity.Methods: The presence of GR polymorphisms was assessed in healthy controls (n = 5033), and in RA patients (n = 368). A second control group (n = 532) was used for confirmation of results. In RA patients, the relationship between GR polymorphisms and disease severity was examined.Results: Carriers of the N363 S and BclI minor alleles had a lower risk of developing RA: odds ratio (OR) = 0.55 (95% confidence interval (CI) 0.32-0.96, P = 0.032) and OR = 0.73 (95% CI 0.58-0.91, P = 0.006), respectively. In contrast, 9β minor allele carriers had a higher risk of developing RA: OR = 1.26 (95% CI 1.00-1.60, P = 0.050). For ER22/23EK minor allele carriers a trend to an increased risk OR = 1.42 (95% CI 0.95-2.13, P = 0.086) was found. All ER22/23EK carriers (32/32) had erosive disease, while only 77% (259/336) of the non-carriers did (P = 0.008). In addition, ER22/23EK carriers were treated more frequently with anti-tumor necrosis factor-alpha (TNFα) therapy (P < 0.05).Conclusions: The minor alleles of the 9β and ER22/23EK polymorphisms seem to be associated with increased predisposition to develop RA. Conversely, the minor alleles of the N363 S and BclI polymorphisms are associated with reduced susceptibility to develop RA. These opposite associations suggest that constitutionally determined GC resistance may predispose to development of auto-immunity, at least in RA, and vice versa. http://repub.eur.nl/res/pub/28432/ 2010-03-03T00:00:00Z Background: Glucocorticoids have an important role in early growth and development. Glucocorticoid receptor gene polymorphisms have been identified that contribute to the variability in glucocorticoid sensitivity. We examined whether these glucocorticoid receptor gene polymorphisms are associated with growth in fetal and early postnatal life.Methods: This study was embedded in a population-based prospective cohort study from fetal life onwards. The studied glucocorticoid receptor gene polymorphisms included BclI (rs41423247), TthIIII (rs10052957), GR-9β (rs6198), N363S (rs6195) and R23K (rs6789 and6190). Fetal growth was assessed by ultrasounds in second and third trimester of pregnancy. Anthropometric measurements in early childhood were performed at birth and at the ages of 6, 14 and 24 months postnatally. Analyses focused on weight, length and head circumference. Analyses were based on 2,414 healthy, Caucasian children.Results: Glucocorticoid receptor gene polymorphisms were not associated with fetal weight, birth weight and early postnatal weight. Also, no associations were found with length and head circumference. Neither were these polymorphisms associated with the risks of low birth weight or growth acceleration from birth to 24 months of age.Conclusions: We found in a large population-based cohort no evidence for an effect of known glucocorticoid receptor gene polymorphisms on fetal and early postnatal growth characteristics. Further systematic searches for common genetic variants by means of genome-wide association studies will enable us to obtain a more complete understanding of what genes and polymorphisms are involved in growth in fetal life and infancy. http://repub.eur.nl/res/pub/27204/ 2009-11-18T00:00:00Z Previously, it has been suggested that hypothalamic-pituitary-adrenal (HPA) axis dysregulation and, as a consequence, increased cortisol levels, is not only a state phenomenon, but may also be a trait phenomenon in mood disorders. Cortisol exerts its effects mainly by binding to the glucocorticoid receptor (GR) and, of particular interest in certain brain regions, the mineralocorticoid receptor (MR). Several GR polymorphisms have been shown to be associated with altered sensitivity of the HPA axis. Recently, the GR polymorphisms BclI and ER2223EK have been associated with unipolar depression in several studies. In addition, the ER2223EK polymorphism seems to be associated with a decreased risk of dementia in healthy individuals. Also, during a depressive episode, carriers of this ER2223EK variant demonstrated a tendency toward better cognition, as measured by divided attention tests. In this overview, currently known clinically relevant GR and MR polymorphisms are discussed in relation to mood disorders (both unipolar depression and bipolar disorder) and cognitive function. http://repub.eur.nl/res/pub/27205/ 2009-11-18T00:00:00Z 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 ER2223EK 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 activity. The associated features of ER2223EK 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 reported 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 sensitivity. 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 rheumatoid arthritis. In this article, studies concerning these clinically relevant GR variants are discussed. http://repub.eur.nl/res/pub/24702/ 2009-10-01T00:00:00Z A female patient developed avascular necrosis of the femoral heads after receiving low doses of glucocorticosteroids (GC) for 3 months. Genotyping of the GC receptor (GR) showed that she was heterozygous for the Bcl-1 allele and heterozygous for the N363S allele. Interestingly, these GR variants are both associated with higher sensitivity to glucocorticoids. It is not known whether the GR gene polymorphisms are causally related to osteonecrosis. However, the presence of these GR variants, as a combination present in only 1 of the normal Caucasian population, seems suggestive. Studies are warranted to investigate the importance of polymorphisms related to GC sensitivity. http://repub.eur.nl/res/pub/24767/ 2009-10-01T00:00:00Z Objective Sensitivity to glucocorticoids is known to be highly variable between individuals and is partly determined by polymorphisms in the glucocorticoid receptor (GR) gene. We investigated the relationship between four GR gene polymorphisms and body composition during puberty and at young adult age. Design An observational study with repeated measurements. Patients Two comparable young Dutch cohorts with a generational difference of about 20 years were investigated. The first cohort consisted of 284 subjects born between 1961 and 1965. Measurements were performed from 13 to 36 years of age. The second cohort consisted of 235 subjects born between 1981 and 1989. Measurements were performed from 8 to 14 years of age. Measurements Associations between height, weight, BMI, fat mass (FM) and fat-free mass and four well-known functional polymorphisms were investigated. Results In boys in the younger cohort, the G-allele of the BclI polymorphism (haplotype 2) was associated with a higher body weight, weight-SDS, BMI, BMI-SDS and FM. These associations were not observed in the older cohort. Irrespective of genotype, the younger cohort showed a significantly higher total FM, body weight and BMI compared with the older cohort. Conclusions Because the associations between the G-allele of the BclI polymorphism in the GR gene and body FM in boys were only found in a healthy young population, but not in a comparable, generally leaner cohort from an older generation, it is suggested that carriers of this polymorphism are likely to be more vulnerable to fat accumulation in today's obesity promoting environment, than noncarriers. http://repub.eur.nl/res/pub/25372/ 2009-06-01T00:00:00Z Context: In patients with multiple sclerosis (MS), glucocorticoids (GCs) might notbesufficiently able to restrain the immune system, possibly due to decreased GC sensitivity. This may be, at least partially, genetically determined. Previously, we reported a more aggressive disease course in patients with the glucocorticoid receptor (GR) gene ER22/23EK polymorphism, which has been shown to decrease GC sensitivity. Objective: In 646 MS patients and 317 healthy controls, we investigated whether haplotypes, including the ER22/23EK polymorphism or the GR 9β polymorphism, which is also associated with a relative GC resistance, were associated with a more aggressive disease course. Patients and Methods: Polymorphisms in the GR gene (9β, ER22/23EK, TthIIII, BclI, and N363S), which have previously been associated with altered GC sensitivity were determined and haplostructure was characterized. We evaluated whether the haplotypes were associated with disease susceptibility and several other disease characteristics. The association with disease progression was analyzed using Cox regression with time to Expanded Disability Status Score 6 as outcome. Results: None of the haplotypes was associated with disease susceptibility, age at onset, or onset type. Haplotype 6 (TthIIII, ER2223EK, and 9β-G) was associated with a more rapid disease progression (hazard ratio 2.3; 95% confidence interval 1.5-3.7; P < 0.001). This seems to result from the presence of ER22/23EK, and not from the 9β and TthIIII polymorphisms. Conclusions: MS patients carrying the haplotype 6 (TthIIII, ER22/23EK, and 9β) have a more aggressive disease course. This is probably due to the presence of the polymorphism ER22/23EK, which causes a decreased GC sensitivity. Copyright http://repub.eur.nl/res/pub/25099/ 2009-01-19T00:00:00Z Objectives: In affective disorders, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is a frequently observed phenomenon. Subtle changes in glucocorticoid receptor (GR) functioning caused by polymorphisms of the GR gene (NR3C1) may be at the base of the altered reaction of the HPA axis to stress and subsequently related to the development and course of affective disorders. The aim of our study is to evaluate associations between GR gene polymorphisms and bipolar disorder (BD). Methods: In this study, 245 patients with BD were interviewed to confirm diagnosis and BD subtype. Data on medication use and sociodemographic details were also collected. The control group consisted of 532 healthy blood donors, from which data on sex and age were collected. To perform genotyping, blood was collected from all patients and healthy controls. Results: A trend was found for a protective effect of the exon 9β polymorphism (p = 0.14) and the TthIII I polymorphism (p < 0.05) on the manifestation of the disease. These effects were significantly influenced by male gender for both polymorphisms. Patients with BD and the A/G variant in exon 9β had significantly fewer manic and hypomanic episodes than noncarriers (p < 0.05). No further associations were found with the other investigated GR gene polymorphisms and BD. These findings were not corrected for multiple comparisons. Conclusions: We conclude that the exon 9β polymorphism and the TthIIII polymorphism of the GR gene may be associated with a protective effect on the clinical manifestation and course in patients with BD. Furthermore, no associations were found between the other studied GR gene polymorphisms and this disease. © 2009 The Authors Journal compilation http://repub.eur.nl/res/pub/25118/ 2009-01-01T00:00:00Z Cortisol has a modulatory influence on cognitive functions in humans. Both impairing and enhancing effects of cortisol administration have been shown for hippocampus-dependent declarative memory, and impairing effects have been shown for prefrontal-cortex-dependent working memory function. Given the high density of glucocorticoid (GC) receptors in the prefrontal cortex, we investigated whether common polymorphisms of the GC receptor (GR) gene (ER22/23EK, N363S, BclI, 9β A3669G) modulate the influence of cortisol administration on working memory. Working memory performance was investigated in 169 subjects on 10 mg hydrocortisone (cortisol) and placebo using an item recognition task. No impairing effect of hydrocortisone treatment became evident. However, a sex × genotype interaction on general working memory performance was revealed (p = 0.02). While female heterozygous carriers of the 9β G allele displayed faster reaction times than the other genotype groups, 9β G heterozygous men were relatively slower. Heritability estimates for memory are roughly 50%, indicating that common genetic polymorphisms have an important impact on cognitive performance. Our results suggest that variants of the GR gene might explain some of the variance attributable to genetic factors. Furthermore, it can be speculated that they modulate the individual vulnerability for memory impairments related to stress-related psychiatric disorders. Copyright http://repub.eur.nl/res/pub/28839/ 2008-12-01T00:00:00Z Context: Glucocorticoids contribute to the development of atherosclerosis. Four polymorphisms in the glucocorticoid receptor (GR) gene have been reported to alter glucocorticoid sensitivity and have been associated with cardiovascular risk factors. Studies on the relationship between these GR variants and cardiovascular disease (CVD) risk, however, have yielded conflicting results. Objective: We sought to determine whether haplotypes based on functional polymorphisms in the GR gene influenced susceptibility to CVD in a high-risk population. Design, Setting, and Participants: In a multicenter cohort study, 1830 patients with heterozygous familial hypercholesterolemia were genotyped for the functional ER22/23EK, N363S, BclI, and 9 variants. We analyzed the combined effect of all GR variants by constructing haplotypes and using a Cox proportional hazards regression model with adjustment for year of birth and smoking. The analyses were stratified for sex. Main Outcome Measures: The primary outcome measure was CVD defined as coronary, cerebral, and peripheral artery disease. Results: A total of 359 men (40.8%) and 224 women (23.6%) had a cardiovascular event. In men, the BclI haplotype was associated with a 34% higher CVD risk (confidence interval 1.02-1.76; P= 0.03) and the 9β haplotype with a 41% higher CVD risk (confidence interval 1.02-1.94; P = 0.04). In women, none of the GR haplotypes was significantly related with CVD. We did not find differences in cardiovascular risk factors between GR haplotypes. Conclusions: In this large cohort of high-risk individuals, two common haplotypes in the GR gene modified CVD susceptibility among men. Copyright http://repub.eur.nl/res/pub/29710/ 2008-10-01T00:00:00Z Objective: Cortisol levels increase with age and hypercortisolism is associated with muscle weakness. This study examines the relationship between cortisol, muscle mass and muscle strength in community-dwelling older persons and the role of genetic variations in the glucocorticoid receptor (GR). Design/patients: The study was conducted within the Longitudinal Ageing Study Amsterdam (LASA, 1992-ongoing), a cohort study in a population-based sample of older persons in the Netherlands. Data were used from 1196 and 1046 participants in the second (1995-1996) and fourth (2001-2002) cycle, respectively. Measurements: Total serum cortisol and free cortisol were measured in the mornings of the second cycle while salivary cortisol sampled early in the morning and late at night were measured in the fourth cycle. The GR gene polymorphisms (ER22/23EK, N363SS, 9β and BclI) were genotyped by Taqman. Appendicular skeletal muscle mass (ASMM) was measured using DXA in the second cycle and 3 years later (third cycle). Grip strength was assessed using a handgrip dynamometer in the second, third, fourth and fifth cycle. Results: A relationship was found between both morning and evening salivary cortisol, and loss of grip strength: participants in the highest quartile of cortisol concentration had a twofold higher risk of loss of grip strength than participants in the lowest quartile (P < 0.05). No relationships were found between serum cortisol (loss of) ASMM, and (loss of) grip strength. The ER22/23EK and N363S-polymorphisms modified the relationships between serum cortisol, ASMM and grip strength, respectively. Due to limited power, these relationships were not significant after stratification for the polymorphisms. Conclusion: High salivary cortisol is associated with a higher risk of loss of grip strength in older persons. GR genotypes modify the relationship between muscle mass and muscle strength. http://repub.eur.nl/res/pub/29743/ 2008-10-01T00:00:00Z A considerable variability in the sensitivity to glucocorticoids (GCs) exists between individuals and these differences have been implicated in the etiology of psychiatric diseases such as depression. Glucocorticoid receptor (GR) gene polymorphisms might account in part for variability in GC responsiveness. We assessed the association between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and markers of glucocorticoid sensitivity in two target tissues (subdermal blood vessels, peripheral leukocytes) in 206 healthy individuals. The BclI GG genotype group showed the least degree of skin blanching, reflecting a lower GC sensitivity of subdermal blood vessels (p = .01). No association between GR genotype and GC sensitivity of peripheral leukocytes was observed. In the same subjects we previously observed an association between GR genotype and GC sensitivity of the pituitary. Polymorphism of the GR gene might constitute a vulnerability or protection factor for stress related disorders and altered GC sensitivity. http://repub.eur.nl/res/pub/29284/ 2008-05-01T00:00:00Z Objective: Elevated glucocorticoid levels are associated with dementia. A glucocorticoid receptor gene variant (ER22/23EK) is related to relative glucocorticoid resistance. We investigated whether the ER22/23EK allele is associated with dementia and structural brain abnormalities. Methods: This study was performed in two prospective population-based cohort studies among elderly. The first study included 6034 participants who were screened for dementia (mean follow-up 5.8 years). The second study included 1011 elderly subjects with an MRI at baseline and follow-up. The ER22/23EK allele was assessed for association with dementia, cognitive function and white matter lesions. Results: The ER22/23EK allele was associated with a decreased risk of dementia. Among non-demented participants, ER22/23EK-carriers had a better performance on psychomotor speed tests than non-carriers. No differences were found in memory function between genotypes. In addition, both presence and progression of white matter lesions was lower in ER22/23EK-carriers. No association was found with brain atrophy on MRI. Conclusions: Our findings suggest a protective effect of the ER22/23EK allele on the risk of dementia and white matter lesions. http://repub.eur.nl/res/pub/32498/ 2008-01-14T00:00:00Z Background: Genetic variants in immunomodulating genes have been suggested to contribute to the risk of cardiovascular disease. Glucocorticoids are important regulators of inflammatory processes and the immune system. Our aim was to determine the contribution of genetic glucocorticoid receptor variants, with different cortisol sensitivities, to the risk of cardiovascular disease. Methods: The study was conducted in a large (n=7983) population-based, prospective cohort of the Rotterdam Study. The mean duration of follow-up was 8.9 years. Measures of cardiovascular disease were incident myocardial infarction, coronary heart disease, high-sensitivity C-reactive protein level, interleukin 6 level, and arteria carotis intima-media thickness. Results: Persons homozygous for haplotype 3, which is a common variant of the glucocorticoid receptor gene, had a more than 2-fold increased risk of myocardial infarction (hazard ratio, 2.1; 95% confidence interval, 1.13-4.07) and an almost 3-fold increased risk of coronary heart disease (hazard ratio, 2.6; 95% confidence interval, 1.40-4.81) compared with nonhomozygous persons. In addition, their C-reactive protein and interleukin 6 levels were higher, and carotis intima-media thickness was greater. No associations were found for the other haplotypes. Conclusions: The glucocorticoid receptor gene haplotype 3 is a common genetic variant and is related to a more active proinflammatory system. This haplotype is associated with the risk of cardiovascular disease and its parameters. These results should be regarded as hypothesis generating until they have been replicated in other studies. Our findings suggest that genetically determined cortisol sensitivity is involved in the pathogenesis of cardiovascular disease and might identify a subgroup at risk. http://repub.eur.nl/res/pub/35145/ 2007-10-15T00:00:00Z Background: Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease. Methods: We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9β) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). Results: Male 9β AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9β AG carriers had elevated ACTH levels (sex by genotype interaction p = .03). Conclusions: We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders. http://repub.eur.nl/res/pub/35804/ 2007-05-01T00:00:00Z Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system, in which unknown environmental factors are thought to trigger disease in genetically susceptible persons. Glucocorticoids (GCs) play an important role in controlling chronic inflammatory diseases, like MS. Three polymorphisms in the glucocorticoid receptor (GR) gene (N363S, ER22/23EK and the Bcl I C/G) have been shown to alter glucocorticoid sensitivity, and therefore may influence disease course. We investigated the influence of these polymorphisms on clinical and MRI parameters. The ER22/23EK polymorphism was associated with a more aggressive MS phenotype, measured both clinically and on MRI. http://repub.eur.nl/res/pub/7000/ 2005-10-19T00:00:00Z Glucocorticoids are hormones, of which the production is increased in response to physical or psychological stress. In basal conditions these hormones are also present in the circulation, but in lower levels. The major glucocorticoid in man is cortisol. The effects of glucocorticoids are mainly mediated by the glucocorticoid receptor, which is present in virtually all tissues throughout the body. This thesis is focused on the gene coding for the glucocorticoid receptor. http://repub.eur.nl/res/pub/13870/ 2005-10-01T00:00:00Z CONTEXT: Interindividual variation in glucocorticoid (GC)-sensitivity can be partly explained by polymorphisms in the GC receptor (GR) gene. The ER22/23EK and N363S polymorphisms have been described to be associated with lower and higher GC sensitivity, respectively. OBJECTIVE AND DESIGN: We examined the basis of this altered GC sensitivity by expressing GR(N363S) and GR(ER22/23EK) in COS-1 cells and investigating their transactivating and transrepressing capacities using a GC response element-luciferase reporter and a p65-activated nuclear factor kappaB-luciferase reporter, respectively. Furthermore, we evaluated the transactivating and transrepressing capacities of the GR in peripheral blood mononuclear lymphocytes of homozygous and heterozygous carriers of these polymorphisms by determining the maximum effect of dexamethasone on transactivation of the GC-induced leucine-zipper and transinhibition of the IL-2 gene by means of real-time RT-PCR. RESULTS: The effects of the polymorphisms in the GR gene previously observed in population studies were also detected at the level of gene expression. The ER22/23EK polymorphism resulted in a significant reduction of transactivating capacity, in both transfection experiments (-14 +/- 5%, P < 0.05) and peripheral blood mononuclear lymphocytes of carriers of this polymorphism (homozygous: -48 +/- 6%, P < 0.01, n = 1; heterozygous: -21 +/- 4%, P = 0.08, n = 3). The N363S polymorphism, associated with increased GC sensitivity, resulted in a significantly increased transactivating capacity, both in vitro (8 +/- 3%; P < 0.02) and ex vivo (homozygous: 204 +/- 19%, P < 0.0001, n = 1; heterozygous: 124 +/- 8%, P = 0.05, n = 3). Neither the ER22/23EK nor the N363S polymorphism seemed to influence the transrepressing capacity of the GR. CONCLUSION: The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting. http://repub.eur.nl/res/pub/13892/ 2005-08-15T00:00:00Z Glucocorticoid sensitivity is an important prognostic factor in pediatric acute lymphoblastic leukemia (ALL). For its antileukemic effect, glucocorticoid binds the intracellular glucocorticoid receptor (GR) subsequently regulating transcription of downstream genes. We analyzed whether genetic variations within the GR gene are related to differences in the cellular response to glucocorticoids. METHODS: In leukemic samples of 57 children, the GR gene was screened for nucleotide variations using a PCR/single-strand conformational polymorphism sequencing strategy. Data were linked to in vivo and in vitro glucocorticoid resistance. RESULTS: No somatic mutations were detected in the GR gene coding region, but six polymorphisms (i.e., ER22/23EK, N363S, BclI, intron mutation 16 bp upstream of exon 5, H588H, and N766N) were identified. In 67% of ALL cases, at least one minor allele of these polymorphisms was detected. Although only borderline significant, the incidence for the N363S polymorphism minor allele was higher (12% versus 6%, P = 0.06) and for the ER22/23EK minor allele lower (4% versus 7.6%, P = 0.1) than in a healthy, comparable population. The different genotypes of the polymorphisms were not related to prednisone resistance. In conclusion, polymorphisms but not somatic mutations in the GR gene coding region occur in leukemic blasts of children with ALL. Our data suggest that these genetic variations are not a major contributor for differences in cellular response to glucocorticoids in childhood ALL. The higher incidence of the N363S minor allele and the lower incidence of the ER22/23EK minor allele in our ALL population as compared with a normal population warrants further research. http://repub.eur.nl/res/pub/13715/ 2005-07-01T00:00:00Z One of the most intriguing polymorphisms in the GR [glucocorticoid (GC) receptor] gene is in codons 22 and 23 [GAGAGG(GluArg) --> GAAAAG (GluLys)]. This polymorphism is associated with a reduced GC sensitivity, a better metabolic and cardiovascular health profile, and an increased survival rate. Recently, Yudt and Cidlowski reported that two different methionine codons in the GR mRNA may be used as initiation codon: AUG-1 and AUG-27, resulting in two isoforms, the GR-A and the GR-B proteins, respectively. They also showed that the GR-B protein had a stronger transactivating effect in transient transfection experiments. In this study, we elucidated the molecular basis for the reduced GC sensitivity by investigating the influence of the ER22/23EK polymorphism on synthesis of GR-A and GR-B by expressing them independently from constructs with and without the polymorphic site. Binding studies with [(3)H]-dexamethasone and transactivation studies showed that, when the ER22/23EK polymorphism is present, approximately 15% more GR-A protein was expressed, whereas total GR levels (GR-A + GR-B) were not affected. These results show that the transcriptional activity in GR(ER22/23EK) carriers is decreased because more of the less transcriptionally active GR-A isoform is formed. This is probably caused by altered secondary mRNA structure. http://repub.eur.nl/res/pub/5943/ 2004-09-01T00:00:00Z OBJECTIVE: A polymorphism near the promoter region of the IGF-I gene has been associated with serum IGF-I levels, age-related decline of serum IGF-I levels, body height, birth weight and intima media thickness in hypertensive subjects. DESIGN AND METHODS: We investigated the association between the length of the IGF-I alleles of this promoter polymorphism and IGF-I levels and body height. Furthermore, we investigated the potential influence of this polymorphism on final height in relationship to the secular trend of individuals born between 1917 and 1945. All subjects were participants of the Rotterdam Study. RESULTS: We observed, in analyses including only homozygous carriers, the highest IGF-I levels in homozygous carriers of the 192-bp allele (18.7 nmol/l +/- 0.6) and homozygous carriers of the 194-bp allele (17.7 nmol/l +/- 1.4). IGF-I levels were significantly lower in individuals with homozygous longer alleles [> 194-bp (12.0 nmol/l +/- 1.2; P < 0.001)] and homozygous shorter alleles [< 192-bp (15.6 nmol/l +/- 1.4; P < 0.05)] compared to homozygous carriers of the 192-bp and the 194-bp allele. In males and females separately, an optimum for serum IGF-I was also observed in homozygous carriers of the 192-bp and 194-bp allele. Only in males, homozygous carriers of the 192-bp allele were significantly taller than homozygous carriers of the shorter alleles (174.9 cm +/- 0.2 vs. 171.5 cm +/- 1.4; P = 0.01). When all subjects genotyped for the IGF-I promoter polymorphism were included in the analysis, a clear optimum for IGF-I levels and body height was observed in carriers of the 192-bp and/or 194-bp allele in the total population. Between 1917 and 1945, a secular trend in body height was observed in our Dutch population. Mean final body height was significantly higher in carriers of the most frequent alleles (192-bp and/or the 194-bp), than carriers of the remaining shorter and longer genotypes (P-trend < 0.01). CONCLUSIONS: In conclusion, we observed an optimum in IGF-I levels and final body height for the 192-bp and 194-bp allele of the IGF-I gene. A gender-specific effect of the IGF-I alleles on body height was observed. The secular trend in body height observed in our elderly Dutch population was similar for the different genotypes; carriers of the 192-bp and/or the 194-bp allele remained significantly taller throughout time. http://repub.eur.nl/res/pub/5978/ 2004-08-01T00:00:00Z We studied 4,963 participants of the population-based Rotterdam Study and found that a genetically determined chronic exposure to low insulin-like growth factor-I (IGF-I) levels is associated with an increased risk for heart failure in elderly patients. http://repub.eur.nl/res/pub/10307/ 2004-01-01T00:00:00Z Most actions of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). The interindividual response to GCs varies considerably, as demonstrated by a variable suppressive response to 0.25-mg dexamethasone (DEX). Several polymorphisms in the gene coding for the GR have been described. It is unclear to what extent the observed response variability is due to GR polymorphisms or to other factors. However, at least three polymorphisms seem to be associated with altered GC sensitivity and changes in body composition and metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to GCs, increased insulin response to DEX, a tendency towards lower bone mineral density, and increased body mass index (BMI). However, other reports found no associations with BMI. Another polymorphism, previously described as a BclI restriction fragment length polymorphism, recently was identified as a C --> G nucleotide change. The G allele also was associated with increased sensitivity to GCs. In middle-aged subjects, the G allele of this BclI polymorphism was associated with increased abdominal obesity, while at older age, a lower BMI was found, accompanied by a tendency towards lower lean body mass. A third polymorphism consists of two linked, single-nucleotide mutations in codons 22 and 23, of which the second mutation results in an amino acid change from arginine (R) to lysine (K). In contrast to the other polymorphisms, this ER22/23EK polymorphism was associated with a relative resistance to GCs. In line with this, ER22/23EK carriers had lower total cholesterol and low-density lipoprotein cholesterol levels as well as lower fasting insulin concentrations and a better insulin sensitivity. C-reactive protein levels were lower in ER22/23EK carriers, as was found in a different population of elderly males. In accordance with this healthy metabolic profile, we found in this population a significantly better survival in ER22/23EK carriers after a 4-year follow-up. GCs also affect the brain. Although a certain level of cortisol is essential for proper brain functioning, excessive GC levels have been shown to negatively affect brain morphology and functions. At older age, we found that the risk of dementia and white matter lesions was lower in ER22/23EK carriers. GCs are also important in the regulation of body fat distribution. At young age, we observed sex-specific differences in body composition. Male ER22/23EK carriers were taller, had more muscle mass, and were stronger than noncarriers. In young females, ER22/23EK carriers had tendencies towards smaller waist and hip circumferences and lower body weight. Another polymorphism (TthIIII) was not associated with altered GC sensitivity. In conclusion, these polymorphisms in the GR gene may contribute considerably to the observed variability in GC sensitivity. As a result, they are associated with several differences in body composition and metabolic factors. http://repub.eur.nl/res/pub/5932/ 2002-01-01T00:00:00Z We investigated whether a polymorphism in codons 22 and 23 of the glucocorticoid (GC) receptor gene [GAGAGG(GluArg) 3GAAAAG(GluLys)] is associated with altered GC sensitivity, anthropometric parameters, cardiovascular risk factors, and sex steroid hormones. In a subgroup of 202 healthy elderly subjects of the Rotterdam Study, we identified 18 heterozygotes (8.9%) for the 22/23EK allele (ER22/23EK carriers). In the highest age group, the number of ER22/23EK carriers was higher (67-82 years, 12.9%) than in the youngest age group (53-67 years, 4.9%; P < 0.05). Two dexamethasone (DEX) suppression tests with 1 and 0.25 mg DEX were performed, and serum cortisol and insulin concentrations were compared between ER22/ 23EK carriers and noncarriers. After administration of 1 mg DEX, the ER22/23EK group had higher serum cortisol concentrations (54.8 ± 18.3 vs. 26.4 ± 1.4 nmol/l, P < 0.0001), as well as a smaller decrease in cortisol (467.0 ± 31.7 vs. 484.5 ± 10.3 nmol/l, P > 0.0001). ER22/23EK carriers had lower fasting insulin concentrations (P > 0.001), homeostasis model assess-ment?insulin resistance (IR) (index of IR, P > 0.05), and total (P > 0.02) and LDL cholesterol concentrations (P > 0.01). Our data suggest that carriers of the 22/ 23EK allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than noncarriers, resulting in a better metabolic health profile. Diabetes 51:3128-3134, http://repub.eur.nl/res/pub/9983/ 2002-01-01T00:00:00Z We investigated whether a polymorphism in codons 22 and 23 of the glucocorticoid (GC) receptor gene [GAGAGG(GluArg) --> GAAAAG(GluLys)] is associated with altered GC sensitivity, anthropometric parameters, cardiovascular risk factors, and sex steroid hormones. In a subgroup of 202 healthy elderly subjects of the Rotterdam Study, we identified 18 heterozygotes (8.9%) for the 22/23EK allele (ER22/23EK carriers). In the highest age group, the number of ER22/23EK carriers was higher (67-82 years, 12.9%) than in the youngest age group (53-67 years, 4.9%; P < 0.05). Two dexamethasone (DEX) suppression tests with 1 and 0.25 mg DEX were performed, and serum cortisol and insulin concentrations were compared between ER22/23EK carriers and noncarriers. After administration of 1 mg DEX, the ER22/23EK group had higher serum cortisol concentrations (54.8 +/- 18.3 vs. 26.4 +/- 1.4 nmol/l, P < 0.0001), as well as a smaller decrease in cortisol (467.0 +/- 31.7 vs. 484.5 +/- 10.3 nmol/l, P < 0.0001). ER22/23EK carriers had lower fasting insulin concentrations (P < 0.001), homeostasis model assessment- insulin resistance (IR) (index of IR, P < 0.05), and total (P < 0.02) and LDL cholesterol concentrations (P < 0.01). Our data suggest that carriers of the 22/23EK allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than noncarriers, resulting in a better metabolic health profile.