Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita

• Ano de defesa: 2019
• Autor(a) principal: Thais Ramos Villela
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; MED - DEPARTAMENTO DE PEDIATRIA; Programa de Pós-Graduação em Ciências da Saúde - Saúde da Criança e do Adolescente; UFMG
• Palavras-chave em Português: Receptor de glicocorticoide; Polimorfismos do gene do receptor de glicocorticoide; SNPs; Hiperplasia adrenal congênita; Glucocorticoides; Polimorfismo de Nucleotídeo Único; Polimorfismo Genético; Hiperplasia Suprarrenal Congênita
• Link de acesso: http://hdl.handle.net/1843/38469

The mainstay treatment in the classic forms of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is chronic glucocorticoid therapy. Since it´s not possible to reproduce the physiological secretion of cortisol, one of the difficulties of the treatment is to find the adequate dose of glucocorticoid to inhibit excess androgen production, but that is not excessive, and avoid potential side effects, which is difficult in clinical practice. Many factors may hinder the therapeutic response. Among these possible factors, evidence has suggested that polymorphisms (SNPs) of the NR3C1 gene, which encodes the glucocorticoid (GR) receptor, would be responsible for a genetically determined set point for glucocorticoid sensitivity. The aim of this study was to determine the frequency of SNPs, previously associated to glucocorticoid sensitivity, in patients with CAH due to 21OHD and compare to general population. We analyzed 265 subjects: 102 patients with 21OHD, mean age 8,95 years (IQ: 2,13-17,95), and 163 controls, mean age 31 years (IQ: 27-41). All patients and controls were genotyped, and their haplotype block were estimated, for BclI (rs41423247), N363S (rs56149945), ER22/23EK (rs6189 and rs6190), ThtIII (rs10052957) and 9β (rs6198). Hardy-Weinberg equilibrium was observed in all SNPs. SNP frequencies in patients, measured by minor allele frequency, were BclI 26.0%, N363S 0.5%, ER22/23EK 2.5%, ThtIII 32.8% and 9β 6.2%, without any significant difference between patients and controls (chi-square test). The frequencies of most NR3C1 polymorphisms genotyped were similar to European population researched in 1000 Genomes Project. The heterozygous genotype (GA) for ThtIII was significant higher in patients (OR: 2.186; p: 0,004), while heterozygous genotype for BclI (CG) was significant higher in controls (OR: 0.581; p: 0,049). Besides that, the “T,G,T,C,C,G” haplotype, that contains only the BclI SNP, was more common in control group (OR 0.56; p: 0,017). Our study demonstrates higher frequencies of heterozygous genotype for ThtIII in patients with 21OHD, compared to the healthy group that had higher frequencies of heterozygous genotype for BclI and for the haplotype with only this SNP. The SNP ThtIII was previously associated with a relative resistance to glucocorticoids and a healthy metabolic profile. These finds suggests that some patients with CAH due to 21OHD could present some degree of glucocorticoid resistance and could require higher doses of glucocorticoid to inhibit androgen production, than that established based on the healthy population.