Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | http://hdl.handle.net/1843/38469 |
Resumo: | 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. |
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Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênitaFrequencies of NR3C1 polymorphisms associated to glucocorticoid sensitivity in patients with congenital adrenal hyperplasiaReceptor de glicocorticoidePolimorfismos do gene do receptor de glicocorticoideSNPsHiperplasia adrenal congênitaGlucocorticoidesPolimorfismo de Nucleotídeo ÚnicoPolimorfismo GenéticoHiperplasia Suprarrenal CongênitaThe 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.A reposição hormonal com glicocorticoides é a base do tratamento da hiperplasia adrenal congênita (HAC), na forma clássica por deficiência de 21-hidroxilase (21OHD). Como não há possibilidade de reprodução exata da secreção fisiológica de cortisol, uma das dificuldades do tratamento é encontrar a dose adequada de glicocorticoide para inibir o excesso de produção androgênica, mas que não seja excessiva e capaz de provocar efeitos adversos, o que na prática constitui um desafio. Muitos fatores podem dificultar a resposta terapêutica. Entre esses possíveis fatores, evidências tem sugerido que polimorfismos (SNPs) do gene NR3C1, que codifica os receptores de glicocorticoide (GR), seriam responsáveis por um set point para a sensibilidade aos glicocorticoides, geneticamente determinado. O objetivo deste estudo foi determinar a frequência dos polimorfismos associados à sensibilidade aos glicocorticoides, mais estudados até o momento, em pacientes com HAC por 21OHD na forma clássica e comparar com um grupo controle. Foram estudados 265 indivíduos: 102 pacientes com 21OHD, mediana de idade 8,95 anos (IQ: 2,13-17,95), e 163 controles, mediana de idade 31 anos (IQ: 27-41). Todos os pacientes e controles foram genotipados e seus haplótipos estimados para os SNPs BclI (rs41423247), N363S (rs56149945), ER22/23EK (rs6189 and rs6190), ThtIII (rs10052957) e 9β (rs6198). Todos os polimorfismos estavam em equilíbrio de Hardy-Weinberg. As frequências dos SNPs nos pacientes, mensuradas pela frequência do alelo menor, foram: BclI 26.0%, N363S 0.5%, ER22/23EK 2.5%, ThtIII 32.8% e 9β 16.2%, sem diferença significativa entre pacientes e controles (teste do qui-quadrado). A frequência da maior parte dos SNPs genotipados foi semelhante ao encontrado na população europeia, na comparação com o Projeto 1000 Genomas. O SNP ThtIII, em heterozigose (GA), foi mais prevalente nos pacientes (OR: 2.186; p: 0,004), enquanto o BclI, também em heterozigose (CG), foi mais prevalente nos controles (OR: 0.581; p: 0,049). Além disso, o haplótipo “T,G,T,C,C,G”, que contém apenas o SNP BclI, foi mais frequente no grupo controle (OR 0.56; p: 0,017). Nesse estudo foi encontrada maior frequência do SNP ThtIII, em heterozigose, nos pacientes com 21OHD, comparados ao grupo controle. O ThtIII tem sido associado a maior resistência glicocorticoide e, também, a um perfil metabólico mais saudável. No grupo controle foi encontrada maior frequência do BclI e do haplótipo que o contém isoladamente, ambos relacionados a maior sensibilidade glicocorticoide. Estes achados sugerem que uma parcela dos pacientes com HAC por 21OHD poderia apresentar algum grau de resistência aos glicocorticoides e, consequentemente, necessitar de doses mais elevadas de reposição do que o estabelecido para a população saudável, para inibir a produção androgênica.Universidade Federal de Minas GeraisBrasilMED - DEPARTAMENTO DE PEDIATRIAPrograma de Pós-Graduação em Ciências da Saúde - Saúde da Criança e do AdolescenteUFMGIvani Novato Silvahttp://lattes.cnpq.br/8973828929584707Marcos José Burle de AguiarTânia Maria Barreto RodriguesThais Ramos Villela2021-10-21T17:56:21Z2021-10-21T17:56:21Z2019-02-12info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/1843/384690000-0001-7133-863Xporhttp://creativecommons.org/licenses/by-nc-nd/3.0/pt/info:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMG2021-10-21T17:56:24Zoai:repositorio.ufmg.br:1843/38469Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oairepositorio@ufmg.bropendoar:2021-10-21T17:56:24Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.none.fl_str_mv |
Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita Frequencies of NR3C1 polymorphisms associated to glucocorticoid sensitivity in patients with congenital adrenal hyperplasia |
title |
Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita |
spellingShingle |
Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita Thais Ramos Villela Receptor de glicocorticoide Polimorfismos do gene do receptor de glicocorticoide SNPs Hiperplasia adrenal congênita Glucocorticoides Polimorfismo de Nucleotídeo Único Polimorfismo Genético Hiperplasia Suprarrenal Congênita |
title_short |
Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita |
title_full |
Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita |
title_fullStr |
Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita |
title_full_unstemmed |
Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita |
title_sort |
Prevalência de polimorfismos do gene NR3C1 relacionados à sensibilidade glicocorticoide em pacientes com hiperplasia adrenal congênita |
author |
Thais Ramos Villela |
author_facet |
Thais Ramos Villela |
author_role |
author |
dc.contributor.none.fl_str_mv |
Ivani Novato Silva http://lattes.cnpq.br/8973828929584707 Marcos José Burle de Aguiar Tânia Maria Barreto Rodrigues |
dc.contributor.author.fl_str_mv |
Thais Ramos Villela |
dc.subject.por.fl_str_mv |
Receptor de glicocorticoide Polimorfismos do gene do receptor de glicocorticoide SNPs Hiperplasia adrenal congênita Glucocorticoides Polimorfismo de Nucleotídeo Único Polimorfismo Genético Hiperplasia Suprarrenal Congênita |
topic |
Receptor de glicocorticoide Polimorfismos do gene do receptor de glicocorticoide SNPs Hiperplasia adrenal congênita Glucocorticoides Polimorfismo de Nucleotídeo Único Polimorfismo Genético Hiperplasia Suprarrenal Congênita |
description |
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. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-02-12 2021-10-21T17:56:21Z 2021-10-21T17:56:21Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1843/38469 0000-0001-7133-863X |
url |
http://hdl.handle.net/1843/38469 |
identifier_str_mv |
0000-0001-7133-863X |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
http://creativecommons.org/licenses/by-nc-nd/3.0/pt/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
http://creativecommons.org/licenses/by-nc-nd/3.0/pt/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
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 |
publisher.none.fl_str_mv |
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 |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
instname_str |
Universidade Federal de Minas Gerais (UFMG) |
instacron_str |
UFMG |
institution |
UFMG |
reponame_str |
Repositório Institucional da UFMG |
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Repositório Institucional da UFMG |
repository.name.fl_str_mv |
Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
repository.mail.fl_str_mv |
repositorio@ufmg.br |
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1816829775033925632 |