Pediatric Endocrinology Division, Hospital das Clínicas da Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.
Pediatric Endocrinology Division, Hospital das Clínicas da Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil; Department of Pediatrics, Medical School, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.
Mol Cell Endocrinol. 2021 Oct 1;536:111399. doi: 10.1016/j.mce.2021.111399. Epub 2021 Jul 21.
Lifelong glucocorticoid (GC) replacement is the mainstay treatment of congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency (21-OHD). Challenges posed by therapeutic management of these patients are well known, but novel insights into the variability in clinical response to GC highlight a role for single nucleotide polymorphisms (SNPs) of the glucocorticoid receptor gene (NR3C1).
To assess whether six commonly studied NR3C1 SNPs, which were previously associated with modified response to GC, are associated with CAH. We further assessed the linkage disequilibrium (LD) among these NR3C1 SNPs and their combination into haplotypes.
Genotypes were determined by Taqman allele discrimination assays for Tth111I (rs10052957), ER22 (rs6189), 23 EK (rs6190), N363S (rs56149945), BclI (rs41423247) and 9β (rs6198) in a Brazilian cohort of 102 unrelated 21-OHD patients and 163 unrelated healthy subjects (controls). Haplotypes were estimated using Haplo.stats, and LD among SNPs using Haploview.
Heterozygous subjects for Tth111I were more frequent in 21-OHD patients (P = 0.004), while heterozygous for BclI were more frequent in controls (P = 0.049). We found a strong LD among the six NR3C1 SNPs, and four out of six common haplotypes contained the Tth111I-variant. Although we found no significant differences in overall haplotype analysis, the BclI-haplotype was less frequent among 21-OHD patients (P = 0.0180).
BclI-haplotype was less common and heterozygous for Tth111I were more frequent in 21-OHD patients, while heterozygous for BclI were more frequent in controls. Our novel findings may contribute to further clinical studies on the prognostic value of NR3C1 haplotypes towards individualized treatment for 21-OHD patients.
由于经典 21-羟化酶缺乏症（21-OHD），终生糖皮质激素（GC）替代疗法是先天性肾上腺增生症（CAH）的主要治疗方法。这些患者治疗管理带来的挑战众所周知，但 GC 治疗反应的可变性方面的新见解突出了糖皮质激素受体基因（NR3C1）单核苷酸多态性（SNP）的作用。
评估先前与 GC 反应改变相关的六个常见 NR3C1 SNPs 是否与 CAH 相关。我们进一步评估了这些 NR3C1 SNPs 之间的连锁不平衡（LD）及其组合成单倍型。
通过 Taqman 等位基因区分测定法，在 102 名无关的 21-OHD 患者和 163 名无关的健康受试者（对照组）中确定 Tth111I（rs10052957）、ER22（rs6189）、23EK（rs6190）、N363S（rs56149945）、BclI(rs41423247) 和 9β(rs6198) 的基因型。使用 Haplo.stats 估计单倍型，使用 Haploview 评估 SNPs 之间的 LD。
Tth111I 杂合子在 21-OHD 患者中更为常见（P=0.004），而 BclI 杂合子在对照组中更为常见（P=0.049）。我们发现六个 NR3C1 SNPs 之间存在很强的 LD，六个常见单倍型中有四个包含 Tth111I 变体。尽管我们在总体单倍型分析中没有发现显著差异，但 BclI 单倍型在 21-OHD 患者中较少见（P=0.0180）。
BclI 单倍型在 21-OHD 患者中较少见，Tth111I 杂合子在 21-OHD 患者中更为常见，而 BclI 杂合子在对照组中更为常见。我们的新发现可能有助于进一步研究 NR3C1 单倍型对 21-OHD 患者个体化治疗的预后价值。
