Low Prevalence of the N363S Polymorphism of the Glucocorticoid Receptor in South Asians Living in the United Kingdom

Syed, Akheel A.; Irving, Julie; Redfern, Christopher P.F.; Hall, Andrew G.; Unwin, Nigel; White, Martin; Bhopal, Raj; Alberti, K. G. M. M.; Weaver, Jolanta U.

doi:10.1210/jc.2003-030995

Cited by 32 publications

(18 citation statements)

References 29 publications

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“…Our data are in accordance to studies in randomly selected European populations, which have reported a frequency of the 363S allele of 3-7% (20,(26)(27)(28)(29). Interestingly, we observed no 363S allele in Brazilian subjects of Asian origin, similar to a study in South Asian subjects living in the United Kingdom, in which the 363S allele frequency was very low (0.3%) (30). Recently, the p.N363S polymorphism was neither detected in a Japanese population (31) nor in Chinese Han individuals, a subset of Asian-origin population (32).…”

Section: Resultssupporting

confidence: 91%

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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Section: Resultssupporting

confidence: 91%

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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“…The observed allele frequencies were consistent with those reported elsewhere for Caucasian populations [11][12][13][14] . The distribution of the alleles and genotypes did not differ between control and patient groups (supplementary materials, Table 3).…”

Section: Resultssupporting

confidence: 91%

IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn’s disease location

Sánchez

Lévy²,

Costea³

et al. 2009

WJG

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AIM:To determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor (GR), the tumor necrosis factor (TNF)-α and the interleukin (IL)-10 in childhood Crohn's disease (CD) and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes. METHODS:Ten variants in GR, TNF-α and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin. RESULTS:For the GR polymorphisms (R23K and N363S) and IL-10 variants in the 5'flanking region (-1082 G > A, -819 T > C and -592 A > C), no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians (GCC, ACC and ATA) and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-α gene (-1031 T > C, -863 A > C, -857 T > C, -308 A > G and -238 A > G) revealed a significant overrepresentation of homozygous -1031 CC among CD patients (OR = 9.9) and an association with the colonic location. For TNF-α, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively.CONCLUSION: This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.

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“…21,22) In the coding region, a novel nonsynonymous variation, 420GÀT (Lys140Asn), was detected in exon 2. 24) Their report and our present data clearly indicate that ethnic dierences between Asian and other populations exist for the Asn363Ser polymorphism. The electropherograms of the variation is shown in Fig.…”

Section: Resultssupporting

confidence: 74%

Novel Genetic Polymorphisms in the NR3C1 (Glucocorticoid receptor) Gene in a Japanese Population

Koyano¹,

Saito²,

Sai³

et al. 2005

Drug Metabolism and Pharmacokinetics

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Glucocorticoid receptor, encoded by NR3C1, is a transcriptional regulator of many drug metabolizing enzymes and anti-inflammatory molecules. In order to identify genetic variations of the NR3C1 gene, genomic DNA from 265 Japanese individuals was sequenced. Fifty genetic polymorphisms were identified, including 32 novel ones [3 were in coding exons, 17 in the introns, 4 in the 5'-untranslated region (UTR), and 8 in the 5'-flanking region]. The novel nonsynonymous variation was 420G>T (Lys140Asn), and the allele frequency was 0.004. We did not detect any nonsynonymous polymorphism reported previously in other races, including a relatively frequent SNP Asn363Ser found in Caucasians and African-Americans. Thus, ethnic differences between Japanese and other races are suggested to exist in NR3C1.

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Low Prevalence of the N363S Polymorphism of the Glucocorticoid Receptor in South Asians Living in the United Kingdom

Cited by 32 publications

References 29 publications

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

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

IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn’s disease location

Novel Genetic Polymorphisms in the NR3C1 (Glucocorticoid receptor) Gene in a Japanese Population

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