Souza Manoel Carlos L A, Martins Clarissa S, Silva-Junior Ivan M, Chriguer Rosangela S, Bueno Ana C, Antonini Sonir R, Silva Wilson Araújo, Zago Marco A, Moreira Ayrton C, Castro Margaret de
Department of Internal Medicine, School of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
epartment of Pediatrics, FMRP-USP, Ribeirao Preto, SP, Brazil.
Arq Bras Endocrinol Metabol. 2014 Feb;58(1):53-61. doi: 10.1590/0004-2730000002868.
The Brazilian population has heterogeneous ethnicity. No previous study evaluated NR3C1 polymorphisms in a Brazilian healthy population.
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.
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).
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.
巴西人口种族构成具有异质性。此前尚无研究评估巴西健康人群中NR3C1基因多态性。
我们评估了高加索、非洲和亚洲血统的巴西人（n = 380）的NR3C1基因多态性。在一个亚组（n = 40）中，我们将基因型与糖皮质激素（GC）敏感性进行了比较，糖皮质激素敏感性此前通过地塞米松（DEX）抑制试验后的血浆（PF）和唾液（SF）皮质醇、GC受体结合亲和力（Kd）以及伴刀豆球蛋白A刺激的单核细胞增殖的DEX - 50%抑制率（IC50）进行评估。通过实时聚合酶链反应（Real - Time PCR）进行p.N363S（rs6195）、p.ER22/23EK（rs6189 - 6190）和BclI（rs41423247）等位基因鉴别。通过聚合酶链反应（PCR）扩增外显子3至9以及外显子/内含子边界并进行测序。
基因型频率（%）如下：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），以及rs72542757（n = 137；CC：99.3/CG：0.7）。rs67300719和rs72542757仅在亚洲后裔中发现，其中不存在p.N363S和p.ER22/23EK。p.ER22/23EK仅在高加索后裔中观察到。除了亚洲人群中的rs6188和rs258751以及非洲人群中的p.N363S外，观察到哈迪 - 温伯格平衡。各基因型组之间的Kd、IC50、基线以及DEX后的PF或SF无差异。然而，BclI基因型之间抑制PF或SF的平均DEX剂量存在差异（P = 0.03）。与GC携带者（0.47 ± 0.1 mg）和CC携带者（0.47 ± 0.2 mg）相比，GG携带者（0.7 ± 0.2 mg）的DEX剂量更高。
巴西人群中NR3C1基因多态性的基因型频率与全球人群相似。此外，BclI基因多态性与垂体 - 肾上腺轴GC敏感性改变有关。
