Effect of glucocorticoid receptor gene polymorphisms in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a postinfectious immune-mediated polyneuroradiculopathy in which host factors influence disease susceptibility and clinical course. Single-nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR) gene influence the sensitivity to glucocorticoids and are related to both microbial colonization and susceptibility to develop auto-immune disease. This genetic variation may therefore also influence the chance to develop GBS. In this study, we genotyped 318 GBS patients and 210 control subjects for five known SNPs in the GR gene. We could distinguish six different GR haplotypes of which two carried the BclI polymorphism: haplotype 1, which consists of the minor allele of BclI in combination with the common variant of TthIIII and haplotype 2, which carries the minor allele of BclI as well as the minor allele of TthIIII. The GR haplotypes were not related to susceptibility to develop GBS. Carriers of haplotype 2 had more frequently preceding diarrhea, serum antibodies to GM1 and GD1a, and more severe muscle weakness at entry. Haplotype 1 carriers had a significantly better prognosis. In conclusion, GR haplotypes are not a susceptibility factor for GBS. However, haplotypes carrying the minor allele of the BclI polymorphism were related to the phenotype and outcome of GBS.

Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance.

Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene (GR, NR3C1). GR polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GR SNP (rs10482605), located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GR SNPs to further characterize GR haplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a A/G SNP in exon 9beta (rs6198), associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GR SNPs in linkage disequilibrium are responsible for both regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression.

Expression of the glucocorticoid receptor and its isoforms in relation to glucocorticoid resistance in childhood acute lymphocytic leukemia.

In vitro prednisolone resistance is a poor prognostic factor in the treatment of childhood acute lymphoblastic leukemia (ALL). In a cohort of 54 children with ALL, a lower expression of the glucocorticoid receptor (GR), but not the relative expression levels of the GR-alpha, GR-beta and GR-P isoforms, was associated with in vitro prednisolone resistance.

Validation and reference ranges of hair cortisol measurement in healthy children.

BACKGROUND: Cortisol is produced in a circadian rhythm controlled by the hypothalamus-pituitary-adrenal axis, making it cumbersome to measure long-term cortisol exposure. Hair has proven to be a reliable matrix for long-term cortisol measurement in adults and can be used as diagnostic tool for (cyclic) Cushing's syndrome. The diagnostic applicability in children has not been studied, nor have the effects of development and hair care been evaluated in children. We aimed to establish reference ranges of hair cortisol concentrations (HCC) in healthy children and to evaluate the effects of age, gender, puberty and characteristics of hair care. METHODS: In 128 healthy children aged 4-14 years, HCC were measured in a small 3-cm hair lock from the back of the head. RESULTS: HCC increased with age (p = 0.04) up to age 10 years, with a mean of 5.0, 5.8, 6.8 and 8.5 pg/mg at age 4-5, 6-7, 8-9 and 10-14 years, respectively. Children aged 4-7 years had significantly lower HCC compared to healthy adults (p = 0.007). We did not find any influence of gender, puberty or hair care characteristics on hair cortisol. CONCLUSION: HCC can be reliably measured in childhood, and reference ranges increase with age. HCC in children are not dependent on hair care or hair characteristics.

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.

Polymorphisms of the glucocorticoid receptor and avascular necrosis of the femoral heads after treatment with corticosteroids.

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.

A glucocorticoid receptor gene haplotype (TthIII1/ER22/23EK/9beta) is associated with a more aggressive disease course in multiple sclerosis.

CONTEXT: In patients with multiple sclerosis (MS), glucocorticoids (GCs) might not be sufficiently 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 9beta 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 (9beta, 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 9beta-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 9beta and TthIIII polymorphisms. CONCLUSIONS: MS patients carrying the haplotype 6 (TthIIII, ER22/23EK, and 9beta) have a more aggressive disease course. This is probably due to the presence of the polymorphism ER22/23EK, which causes a decreased GC sensitivity.