Identification of the <i>Bcl</i>I polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids <i>in vivo</i> and body mass index

Rossum, Elisabeth F.C. van; Koper, Jan W.; Beld, Annewieke W. van den; Uitterlinden, André G.; Arp, Pascal P.; Ester, Wietske A.; Janssen, Joseph A M J L; Brinkmann, Albert O.; Jong, Frank H. de; Grobbee, Diederick E.; Pols, Huibert A. P.; Lamberts, Steven W. J.

doi:10.1046/j.1365-2265.2003.01888.x

Cited by 295 publications

(286 citation statements)

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“…Cortisol, MR, and GR SNPs in mental performance M Kuningas et al Previously, it has been shown that the GR gene polymorphisms alter HPA-axis responsiveness and thereby cortisol sensitivity. The ER22/23EK variation has been associated with resistance to cortisol (van Rossum et al, 2002), whereas the N363S and BclI polymorphisms were shown to increase the sensitivity to cortisol (Huizenga et al, 1998;van Rossum et al, 2002van Rossum et al, , 2003. We reasoned, that the increased resistance to cortisol attained by the ER22/23EK variant would protect against the damaging effects of highcortisol levels on cognitive decline and depression, whereas increased cortisol sensitivity would have opposite effects.…”

Section: Discussionmentioning

confidence: 99%

“…In the MR gene, the 215G/C and I180V single-nucleotide polymorphisms (SNPs) have been shown to change cortisol signaling in vitro (Arai et al, 2003), whereas in the GR gene the ER22/23EK, N363S, and BclI SNPs have been shown to change HPA-axis reactivity after a dexamethasone suppression test or a psychosocial stressor (Huizenga et al, 1998;van Rossum et al, 2002van Rossum et al, , 2003. In addition, the ER22/23EK variant has been associated with major depression in two studies (van Rossum et al, 2006;van West et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Mental Performance in Old Age Dependent on Cortisol and Genetic Variance in the Mineralocorticoid and Glucocorticoid Receptors

Kuningas

Rijk

Westendorp

et al. 2006

Neuropsychopharmacol

120

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Depression and cognitive decline have been associated with changes in circulating cortisol concentrations. Cortisol exerts its functions through mineralocorticoid (MR) and glucocorticoid (GR) receptors. However, data on the influence of variations in the MR and GR genes on depressive symptoms and cognitive functioning in older adults are scarce. Therefore, we explored the impact of MR-215G/C, MR-I180V, GR-ER22/23EK, GR-N363S, and GR-BclI polymorphisms on these end points in the population-based Leiden 85-plus Study. This prospective study includes 563 participants aged 85 years and older, with a mean follow-up of 4.2 years. In this study, high morning cortisol levels (per 1 SD cortisol) associated with impairments in global cognitive functioning (p ¼ 0.002) at baseline (age 85). These impairments were mainly attributable to lower attention (p ¼ 0.057) and slower processing speed (p ¼ 0.014). Similar effects were also observed during follow-up (age 85-90), where participants with higher cortisol levels (per 1 SD cortisol) had impaired global cognitive functioning (p ¼ 0.003), as well as impairments in attention (p ¼ 0.034) and processing speed (p ¼ 0.013). Changes in depressive symptoms were observed for the MR-I180V single-nucleotide polymorphism (SNP), where during follow-up the prevalence of depressive symptoms was higher in the 180V-allele carriers (p ¼ 0.049) compared to noncarriers. Dependent on these polymorphisms, no differences in overall and in specific domains of cognitive functioning were observed. In conclusion, the MR-I180V SNP has a specific effect on depressive symptoms, independent from cognitive functioning, and other polymorphisms in the MR and GR genes. In contrast, these genetic variants in the MR and GR genes do not influence cognitive functioning in old age.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mental Performance in Old Age Dependent on Cortisol and Genetic Variance in the Mineralocorticoid and Glucocorticoid Receptors

Kuningas

Rijk

Westendorp

et al. 2006

Neuropsychopharmacol

120

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“…BclI polymorphism has been associated with increased GC sensitivity determined by skin blanching response to topical GCs and increased cortisol suppression after low-dose DEX (19,38,39). In a large group of Dutch elderly individuals, subjects with the G allele had lower cortisol levels after dexamethasone suppression test as well as a tendency towards a decreased lean body mass and abdominal fat distribution, high blood pressure, altered insulin sensitivity, and cardiovascular risk factors, suggesting hypersensitivity to GC (38).…”

Section: Discussionmentioning

confidence: 99%

“…In a large group of Dutch elderly individuals, subjects with the G allele had lower cortisol levels after dexamethasone suppression test as well as a tendency towards a decreased lean body mass and abdominal fat distribution, high blood pressure, altered insulin sensitivity, and cardiovascular risk factors, suggesting hypersensitivity to GC (38). In 42 blood donors, association between the BclI variant genotype and an increased in vitro sensitivity to GCs was observed by DEX-mediated inhibition of concanavalin-A-stimulated PMBC (40).…”

Section: Discussionmentioning

confidence: 99%

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association

Souza

Martins

Silva-Junior

et al. 2014

Arq Bras Endocrinol Metab

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Objective: The Brazilian population has heterogeneous ethnicity. No previous study evaluated NR3C1 polymorphisms in a Brazilian healthy population. Materials and methods: We assessed NR3C1 polymorphisms in Brazilians of Caucasian, African and Asian ancestry (n = 380). In a subgroup (n = 40), we compared the genotypes to glucocorticoid (GC) sensitivity, which was previously evaluated by plasma (PF) and salivary (SF) cortisol after dexamethasone (DEX) suppression tests, GC receptor binding affinity (K d ), and DEX-50% inhibition (IC 50 ) of concanavalin-A-stimulated mononuclear cell proliferation. p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) allelic discrimination was performed by Real-Time PCR (Polymerase Chain Reaction). Exons 3 to 9 and exon/intron boundaries were amplified by PCR and sequenced. Results: Genotypic frequencies (%) were: rs6195 (n = 380; AA:96.6/AG:3.14/GG:0.26), rs6189-6190 (n = 264; GG:99.6/ GA:0.4), rs41423247 (n = 264; CC:57.9/CG:34.1/GG:8.0), rs6188 (n = 155; GG:69.6/GT:25.7/TT:4.7), rs258751 (n = 150; CC:88.0/CT:10.7/TT:1.3), rs6196 (n = 176; TT:77.2/TC:20.4/CC:2.4), rs67300719 (n = 137; CC:99.3/CT:0.7), and rs72542757 (n = 137; CC:99.3/CG:0.7). The rs67300719 and rs72542757 were found only in Asian descendants, in whom p.N363S and p.ER22/23EK were absent. The p.ER22/23EK was observed exclusively in Caucasian descendants. Hardy-Weinberg equilibrium was observed, except in the Asian for rs6188 and rs258751, and in the African for p.N363S. The K d , IC 50 , baseline and after DEX PF or SF did not differ between genotype groups. However, the mean DEX dose that suppressed PF or SF differed among the BclI genotypes (P = 0.03). DEX dose was higher in GG-(0.7 ± 0.2 mg) compared to GC-(0.47 ± 0.2 mg) and CC-carriers (0.47 ± 0.1 mg). Conclusion: The genotypic frequencies of NR3C1 polymorphisms in Brazilians are similar to worldwide populations. Additionally, the BclI polymorphism was associated with altered pituitary-adrenal axis GC sensitivity. Arq Bras Endocrinol Metab. 2014;58(1):53-61 Keywords NR3C1 genotypes; allelic frequencies; glucocorticoid sensitivity RESUMO Objetivo: Este estudo avalia polimorfismos (SNPs) do NR3C1 na população brasileira, que possui origem étnica heterogênea. Materiais e métodos: SNPs do NR3C1 foram avaliados em brasileiros de ancestralidade caucasiana, africana ou japonesa (n = 380). Em um subgrupo (n = 40), os genótipos foram comparados à sensibilidade aos glicocorticoides (GC), previamente avaliada por cortisol plasmático (PF) e salivar (SF) após supressão com dexametasona (DEX), ensaio de afinidade do receptor ao GC (K d ) e inibição por DEX de 50% da proliferação de mononucleares estimulada por concanavalina-A (IC 50 ). Discriminação alélica de p.N363S (rs6195), p.ER22/23EK (rs6189-6190) e BclI (rs41423247) foi realizada por PCR em tempo real. Éxons 3 a 9 e transições éxon/íntron foram amplificados e sequenciados. Resultados: Frequências genotípicas (%) foram: rs6195 (n = 380; AA:96,6/AG:3,14/GG:0,26), rs6189-6190 (n = 264; GG:99,6/GA:0...

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“…; associated with cortisol levels (BclI) 34,35 ADRA2A Chromosome 10q25 ADRA2ADraI 6.3/6.3+6.3/6.7 (30%) 6.7/6.7 (70%) Unknown (DraI)…”

Section: Discussionmentioning

confidence: 99%

Contribution of several candidate gene polymorphisms in the determination of adiposity changes: results from the Québec Family Study

et al. 2007

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Background: Several candidate genes have been associated with obesity, but very few studies have tested more than one gene simultaneously. Methods: In this study, 15 polymorphisms in 10 candidate genes of obesity were tested for association with changes in adiposity measured over a period of 6-10 years in a maximum of 332 adult subjects with a wide range of adiposity (17.5obody mass index (BMI)o55.6 kg/m 2 ) from the Québec Family Study. Stepwise regression models were used to identify the combination of genes explaining changes in adiposity after adjustment for age (initial value), gender, initial value of the adiposity variable and duration of follow-up. Analyses were carried out in the whole sample and repeated while stratifying on age (o40 and X40 years). Results: In the whole sample, the variance in age-related adiposity changes explained by the candidate gene polymorphisms ranged from 3.1% (BMI, Po0.05) to 8.5% (fat mass (FM), Pp0.0005). The genes retained in the prediction model for changes in FM were leptin (Pp0.05), guanine nucleotide binding protein b3 (Pp0.05), adrenergic receptor b3 (Pp0.05), neuromedin b (Pp0.05) and peroxisome proliferator-activated receptor-g2 (Pp0.10). The effects of the genes were significant in both age groups, but the genes contributing to adiposity changes were different and their effects were stronger in the younger than in the older age group. Conclusion: This study suggests that models including genetic information from several candidate gene polymorphisms can significantly contribute to the changes in adiposity over time, that different genes may act at different ages and that genetic information could be useful for the identification of individuals at high risk for gaining body fat over time.

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Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index

Cited by 295 publications

References 20 publications

Mental Performance in Old Age Dependent on Cortisol and Genetic Variance in the Mineralocorticoid and Glucocorticoid Receptors

Mental Performance in Old Age Dependent on Cortisol and Genetic Variance in the Mineralocorticoid and Glucocorticoid Receptors

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association

Contribution of several candidate gene polymorphisms in the determination of adiposity changes: results from the Québec Family Study

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