Erica L.T. van den Akker

Clinical features associated with glucocorticoid receptor polymorphisms: An overview

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 activity. 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 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, Crohns 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.

Staphylococcus aureus Nasal Carriage Is Associated with Glucocorticoid Receptor Gene Polymorphisms

The aim of this study was to determine whether polymorphisms of the glucocorticoid receptor gene, influencing glucocorticoid sensitivity, are associated with persistent nasal carriage of Staphylococcus aureus. Two nasal swab cultures were obtained from each of 2,929 participants. Subjects were classified as persistent carriers (n=563) if both cultures were positive. GG homozygotes of the exon 9beta polymorphism were associated with a 68% reduced risk of persistent S. aureus nasal carriage, whereas carriers of the codon 23 lysine allele displayed an 80% increased risk. Thus, genotype-dependent variation in the sensitivity to glucocorticoids is associated with tolerance toward staphylococcal nasal colonization.

Glucocorticoid receptor gene and risk of cardiovascular disease

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.

Increased Scalp Hair Cortisol Concentrations in Obese Children

CONTEXT Pathologically increased cortisol exposure induces obesity, but it is not known whether relatively high cortisol within the physiological range is related to childhood obesity. OBJECTIVE The aim of the study was to compare hair cortisol concentrations between obese and normal-weight children. DESIGN We performed an observational case-control study. PARTICIPANTS Twenty obese children (body mass index-SD score [BMI-SDS]>2.3) and 20 age- and sex-matched normal-weight children (BMI-SDS<1.1) aged 8-12 years were recruited. MAIN OUTCOME MEASURES Scalp hair samples from the posterior vertex were collected, and hair cortisol concentrations were measured using ELISA. Body weight, height, and waist circumference were measured. From the obese children, additional data on blood pressure and blood lipid concentrations were collected. RESULTS In both groups, five boys and 15 girls were included; their mean age was 10.8±1.3 vs 10.8±1.2 years (obese vs normal weight; not significant). Body weight, BMI, BMI-SDS, and waist circumference were higher in the obese children compared with the normal-weight children (69.8±17.2 vs 35.5±7.2 kg; 29.6±4.9 vs 16.4±1.6 kg/m2; 3.4±0.5 vs -0.2±0.8 SDS; 94±13 vs 62±6 cm; P<.001 all). Hair cortisol concentration was higher in obese than normal-weight children (median [interquartile range], 25 [17, 32] vs 17 [13, 21] pg/mg; P<.05). CONCLUSIONS Hair cortisol concentration, a measure for long-term cortisol exposure, was higher in obese children than normal-weight children. This suggests long-term activation of the hypothalamus-pituitary-adrenal axis in obese children and may provide a novel target for treatment of obesity in children.

The effect of a short message service maintenance treatment on body mass index and psychological well‐being in overweight and obese children: a randomized controlled trial

Maintaining weight loss results in childhood obesity treatment is difficult to achieve. Self‐management techniques such as self‐monitoring are associated with increased weight loss and maintenance. This study analyzes whether self‐monitoring of lifestyle behaviours through a short message service maintenance treatment (SMSMT) via mobile phones with personalized feedback positively effects weight, lifestyle behaviours and psychological well‐being in obese children.

Predictors of Participant Dropout at Various Stages of a Pediatric Lifestyle Program

OBJECTIVE: To evaluate baseline predictors of drop out at various stages in a lifestyle intervention for overweight and obese children. PATIENTS AND METHODS: Children and their families (N = 248) (aged 8–14 years) attended a lifestyle intervention. At baseline, we assessed anthropometric and demographic data, measured competence and behavioral problems, and family functioning. Dropout rates were analyzed at various stages in treatment with logistic regression analyses. RESULTS: Children who had mothers of non-white descent, who had higher BMI SDS, who participated in fewer activities, who did not have breakfast regularly, and who did not live in families with a static adaptability structure were more likely to drop out between 0 and 12 months. Different characteristics predicted dropout at various stages of treatment: (1) having an ethnic minority status and being older predicted dropping out between 0 and 3 months; (2) having a nonwhite mother, participating in fewer activities, having higher delinquency scores, and not presenting the family as extremely positive predicted dropping out between 3 and 9 months; and (3) having a higher BMI SDS, having fewer social problems, and not living in families with a static adaptability structure predicted dropping out between 9 and 12 months of treatment. CONCLUSIONS: The results indicate diffrerent characteristics predict dropping out from a pediatric lifestyle program at various stages in treatment. These findings highlight the need for tailored interventions that target different characteristics at various stages of treatment to reduce drop out rates.

Determinants of hair cortisol and hair cortisone concentrations in adults

BACKGROUND The analysis of hair cortisol concentrations (HairF) is a promising new tool for the assessment of long-term cortisol. With the development of multiple steroid analyses by means of liquid chromatography tandem-mass spectrometry (LC-MS/MS), the analysis of cortisone in hair (HairE) has also been facilitated. However, the influence of various types of determinants on HairF and HairE is still largely unknown. This study systematically assesses the influence of sociodemographic, health, lifestyle, and hair (treatment) characteristics on HairF and HairE. METHOD Data of 760 psychiatrically healthy participants (71.8% female, mean age 45.89 years) of the Netherlands Study of Depression and Anxiety (NESDA) were used. HairF and HairE were measured in the proximal 3 cm of scalp hair, using LC-MS/MS. FINDINGS HairF and HairE strongly correlated. In simple linear regressions, HairF and HairE were higher in older age, in presence of diabetes mellitus, and in men compared to women. More frequent washing of the hair was associated with lower HairF and HairE. Darker hair colours were associated with higher HairF and HairE. An effect of season and of use of oral contraceptives was found for HairF. After full mutual adjustment, only age, presence of diabetes mellitus, hair washing frequency, and season remained significant determinants of HairF. INTERPRETATION This large-scale study shows that HairF and HairE are upregulated in older age and in the presence of diabetes mellitus. This suggests that these levels are important for somatic health and should be taken into account when using hair corticosteroid analysis in future studies.

Glucocorticoid receptor polymorphisms and haplotypes and their expression in health and disease.

Cortisol is involved in many physiological processes, including immunosuppressive and anti-inflammatory actions, and therefore cortisol and its synthetic analogs are widely used to treat a large number of diseases. In glucocorticoid treatment, a large variability of clinical responses is observed. This variability may, in part, be ascribed to genetic variation in the glucocorticoid receptor (GR) gene. In this review we present a catalogue of the various single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor gene and their consequences for human health and disease. Many different GR SNP association studies have been described. However, most studies come down to only a few SNPs reported with different annotations. In this review we clarified these different annotations to uniform names. Most associations between GR SNPs and phenotype have been found in body composition, metabolism, the cardiovascular system, the immune system and psychiatric illnesses. However, many associations have not been replicated (yet), and future replication studies and meta-analyses are needed. There is a substantial body of evidence for GR SNPs to have effects on clinical phenotype. However, as most SNP frequencies are low and their variation is within the range of the general population, the impact of a single SNP for health and disease in the general population is probably modest. However, in-depth studying of the molecular mechanisms of repeatedly observed clinical associations could lead to new possibilities for drug development. In particular the development of selective glucocorticoid receptor modulators holds promise.

Short message service reduces dropout in childhood obesity treatment: a randomized controlled trial

OBJECTIVE Lifestyle programs can reduce the level of overweight in children; however, maintenance results and adherence to treatment are difficult to achieve. New technologies, such as the Short Message Service (SMS), might be a promising tool for enhancing interventions. The effect of an SMS approach aimed at improving treatment results and reducing dropout rates in a pediatric lifestyle intervention, is explored. METHOD Overweight and obese children (N = 141; age 7-12 years) participating in a lifestyle program were randomly assigned to an intervention group receiving an SMS Maintenance Treatment (SMSMT) for 38 weeks (n = 73) or to a control group receiving no SMSMT (n = 68). Children were asked to send weekly self-monitoring data on exercise, eating behavior, and emotional well-being. In return, they received tailored feedback messages. A differential decrease in BMI was analyzed with repeated measures ANOVA and dropout with logistic regression analysis. RESULTS We found no significant difference in BMI decrease between the two groups after 12 months; however, we showed that the SMSMT group had 3.25 times less probability of dropping out after 1 year (p = .01) than controls. In the first 3 months of SMSMT, the SMSMT completers sent 0.80 SMSs per week, which reduced to 0.50 SMSs in the final 3 months. Younger children sent more SMSs (p = .03). CONCLUSIONS These results indicate that SMSMT is effective in reducing dropout rates from a pediatric lifestyle intervention. Future research should examine the effectiveness of SMSMT on weight management and related psychosocial variables.

Long-term cortisol levels measured in scalp hair of obese patients

In obese subjects a relatively high cortisol output in urine has been observed compared to nonobese individuals. However, cortisol levels in blood, saliva, and urine in association with obesity have been inconsistent across studies, possibly due to the high variability of systemic cortisol levels. Cortisol levels measured in scalp hair provide a marker for long‐term cortisol exposure, and have been associated with cardiovascular disease in an elderly population and to disease course in Cushings disease. We aimed to compare hair cortisol levels between obese patients and nonobese controls.