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Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia

Glucocorticoids (GC) replacement are the mainstay treatment for 21-hydroxylase deficiency (21-OHD), the most common cause of congenital adrenal hyperplasia (CAH), in its classical form. There are novel insights into the genetic basis of the GC action diversity that point to an important role for GC...

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Autores principales: Botelho Barra, Cristina, Villela, Thais Ramos, Soares, Nedstâni de Freitas, Colosimo, Enrico Antônio, Belisário, André Rolim, e Silva, Ana Cristina Simões, Silva, Ivani Novato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9767328/
https://www.ncbi.nlm.nih.gov/pubmed/36538565
http://dx.doi.org/10.1371/journal.pone.0279298
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author Botelho Barra, Cristina
Villela, Thais Ramos
Soares, Nedstâni de Freitas
Colosimo, Enrico Antônio
Belisário, André Rolim
e Silva, Ana Cristina Simões
Silva, Ivani Novato
author_facet Botelho Barra, Cristina
Villela, Thais Ramos
Soares, Nedstâni de Freitas
Colosimo, Enrico Antônio
Belisário, André Rolim
e Silva, Ana Cristina Simões
Silva, Ivani Novato
author_sort Botelho Barra, Cristina
collection PubMed
description Glucocorticoids (GC) replacement are the mainstay treatment for 21-hydroxylase deficiency (21-OHD), the most common cause of congenital adrenal hyperplasia (CAH), in its classical form. There are novel insights into the genetic basis of the GC action diversity that point to an important role for GC receptor (GR) gene polymorphisms, suggesting a possible modulation in occurrence of metabolic disorders, what may be relevant to clinical management of 21-OHD. The aim of this study was to investigate whether the five GR gene polymorphisms Tth111I, ER22, 23EK, BclI, 9β (rs10052957, rs6189, rs6190, rs41423247, rs6198) and their combination into haplotypes are associated to different GC response in a cohort of classic 21-OHD subjects. GR genotype-phenotype associations were explored after a dexamethasone suppression test using very low-doses (VLD-DST), 20 and 40 μg/m². The final sample (n = 28) was selected based on the 102 individuals’ previous genotypes classification, according to literature data of GC sensitivity or resistance. Thus, only patients with GC increased resistance (n = 18) or increased sensitivity (n = 10) profiles were selected. Out of 28 subjects aged 12 (2–34) years enrolled in this study, 75% were females, 75% presented the salt-wasting form (SW) and 25% the simple virilizing form (SV). Subjects who carried Tth111I and 9β, associated or not to the ER22/23EK variants, showed an impaired DST response. Results did not differ significantly according to gender or body mass index. SV subjects with GC hypersensitivity-genotypes showed decreased average cortisol levels compared to those with GC resistance-genotypes (p = 0.0023). The Tth111I + 9β/ Wild or Tth111I + ER22/23EK + 9β/ Wild genotypes were associated to GC resistance in this population. This finding may be relevant given the challenges posed by therapeutic management with GC in CAH.
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spelling pubmed-97673282022-12-21 Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia Botelho Barra, Cristina Villela, Thais Ramos Soares, Nedstâni de Freitas Colosimo, Enrico Antônio Belisário, André Rolim e Silva, Ana Cristina Simões Silva, Ivani Novato PLoS One Research Article Glucocorticoids (GC) replacement are the mainstay treatment for 21-hydroxylase deficiency (21-OHD), the most common cause of congenital adrenal hyperplasia (CAH), in its classical form. There are novel insights into the genetic basis of the GC action diversity that point to an important role for GC receptor (GR) gene polymorphisms, suggesting a possible modulation in occurrence of metabolic disorders, what may be relevant to clinical management of 21-OHD. The aim of this study was to investigate whether the five GR gene polymorphisms Tth111I, ER22, 23EK, BclI, 9β (rs10052957, rs6189, rs6190, rs41423247, rs6198) and their combination into haplotypes are associated to different GC response in a cohort of classic 21-OHD subjects. GR genotype-phenotype associations were explored after a dexamethasone suppression test using very low-doses (VLD-DST), 20 and 40 μg/m². The final sample (n = 28) was selected based on the 102 individuals’ previous genotypes classification, according to literature data of GC sensitivity or resistance. Thus, only patients with GC increased resistance (n = 18) or increased sensitivity (n = 10) profiles were selected. Out of 28 subjects aged 12 (2–34) years enrolled in this study, 75% were females, 75% presented the salt-wasting form (SW) and 25% the simple virilizing form (SV). Subjects who carried Tth111I and 9β, associated or not to the ER22/23EK variants, showed an impaired DST response. Results did not differ significantly according to gender or body mass index. SV subjects with GC hypersensitivity-genotypes showed decreased average cortisol levels compared to those with GC resistance-genotypes (p = 0.0023). The Tth111I + 9β/ Wild or Tth111I + ER22/23EK + 9β/ Wild genotypes were associated to GC resistance in this population. This finding may be relevant given the challenges posed by therapeutic management with GC in CAH. Public Library of Science 2022-12-20 /pmc/articles/PMC9767328/ /pubmed/36538565 http://dx.doi.org/10.1371/journal.pone.0279298 Text en © 2022 Botelho Barra et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Botelho Barra, Cristina
Villela, Thais Ramos
Soares, Nedstâni de Freitas
Colosimo, Enrico Antônio
Belisário, André Rolim
e Silva, Ana Cristina Simões
Silva, Ivani Novato
Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia
title Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia
title_full Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia
title_fullStr Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia
title_full_unstemmed Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia
title_short Pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia
title_sort pharmacogenomic markers of glucocorticoid response in congenital adrenal hyperplasia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9767328/
https://www.ncbi.nlm.nih.gov/pubmed/36538565
http://dx.doi.org/10.1371/journal.pone.0279298
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