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Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study
BACKGROUND AND PURPOSE: Acamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety an...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177536/ https://www.ncbi.nlm.nih.gov/pubmed/35016259 http://dx.doi.org/10.1111/bph.15795 |
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author | Ho, Ming‐Fen Zhang, Cheng Wei, Lixuan Zhang, Lingxin Moon, Irene Geske, Jennifer R. Skime, Michelle K. Choi, Doo‐Sup Biernacka, Joanna M. Oesterle, Tyler S. Frye, Mark A. Seppala, Marvin D. Karpyak, Victor M. Li, Hu Weinshilboum, Richard M. |
author_facet | Ho, Ming‐Fen Zhang, Cheng Wei, Lixuan Zhang, Lingxin Moon, Irene Geske, Jennifer R. Skime, Michelle K. Choi, Doo‐Sup Biernacka, Joanna M. Oesterle, Tyler S. Frye, Mark A. Seppala, Marvin D. Karpyak, Victor M. Li, Hu Weinshilboum, Richard M. |
author_sort | Ho, Ming‐Fen |
collection | PubMed |
description | BACKGROUND AND PURPOSE: Acamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes. EXPERIMENTAL APPROACH: We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3‐month follow‐up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics. KEY RESULTS: Baseline plasma arginine, threonine, α‐aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics‐informed genome‐wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell‐derived forebrain astrocytes showed that a series of genes identified during the metabolomics‐informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes. CONCLUSION AND IMPLICATIONS: These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients. |
format | Online Article Text |
id | pubmed-9177536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91775362022-10-14 Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study Ho, Ming‐Fen Zhang, Cheng Wei, Lixuan Zhang, Lingxin Moon, Irene Geske, Jennifer R. Skime, Michelle K. Choi, Doo‐Sup Biernacka, Joanna M. Oesterle, Tyler S. Frye, Mark A. Seppala, Marvin D. Karpyak, Victor M. Li, Hu Weinshilboum, Richard M. Br J Pharmacol Research Articles BACKGROUND AND PURPOSE: Acamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes. EXPERIMENTAL APPROACH: We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3‐month follow‐up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics. KEY RESULTS: Baseline plasma arginine, threonine, α‐aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics‐informed genome‐wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell‐derived forebrain astrocytes showed that a series of genes identified during the metabolomics‐informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes. CONCLUSION AND IMPLICATIONS: These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients. John Wiley and Sons Inc. 2022-02-08 2022-07 /pmc/articles/PMC9177536/ /pubmed/35016259 http://dx.doi.org/10.1111/bph.15795 Text en © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Ho, Ming‐Fen Zhang, Cheng Wei, Lixuan Zhang, Lingxin Moon, Irene Geske, Jennifer R. Skime, Michelle K. Choi, Doo‐Sup Biernacka, Joanna M. Oesterle, Tyler S. Frye, Mark A. Seppala, Marvin D. Karpyak, Victor M. Li, Hu Weinshilboum, Richard M. Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study |
title | Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study |
title_full | Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study |
title_fullStr | Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study |
title_full_unstemmed | Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study |
title_short | Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study |
title_sort | genetic variants associated with acamprosate treatment response in alcohol use disorder patients: a multiple omics study |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177536/ https://www.ncbi.nlm.nih.gov/pubmed/35016259 http://dx.doi.org/10.1111/bph.15795 |
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