title: NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association.
abstract: OBJECTIVE
  The Brazilian population has heterogeneous ethnicity. No previous study evaluated NR3C1 polymorphisms in a Brazilian healthy population.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, School of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Manoel Carlos L A
authors.initials: MC
authors.lastname: Souza
authors.affiliation: Department of Internal Medicine, School of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Clarissa S
authors.initials: CS
authors.lastname: Martins
authors.affiliation: Department of Internal Medicine, School of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Silva-Junior
authors.affiliation: Department of Internal Medicine, School of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Rosangela S
authors.initials: RS
authors.lastname: Chriguer
authors.affiliation: epartment of Pediatrics, FMRP-USP, Ribeirao Preto, SP, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Bueno
authors.affiliation: epartment of Pediatrics, FMRP-USP, Ribeirao Preto, SP, Brazil.
authors.forename: Sonir R
authors.initials: SR
authors.lastname: Antonini
authors.affiliation: Department of Genetics, FMRP-USP, Ribeirao Preto, SP, Brazil.
authors.forename: Wilson Araújo
authors.initials: WA
authors.lastname: Silva
authors.affiliation: Department of Internal Medicine, School of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Zago
authors.affiliation: Department of Internal Medicine, School of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Ayrton C
authors.initials: AC
authors.lastname: Moreira
authors.affiliation: Department of Internal Medicine, School of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Margaret de
authors.initials: Md
authors.lastname: Castro
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D044466:Asian People / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D001938:Brazil / Q000208:ethnology; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000187:drug effects*; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000172:deficiency* / Q000235:genetics; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D006854:Hydrocortisone