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Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease lacking effective treatments. This is due, in part, to a complex and incompletely understood pathophysiology. To shed light, we conducted untargeted metabolomics on plasma from two independent cross-sectional ALS cohorts versus...

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Autores principales: Goutman, Stephen A, Guo, Kai, Savelieff, Masha G, Patterson, Adam, Sakowski, Stacey A, Habra, Hani, Karnovsky, Alla, Hur, Junguk, Feldman, Eva L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762943/
https://www.ncbi.nlm.nih.gov/pubmed/35088843
http://dx.doi.org/10.1093/brain/awac025
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author Goutman, Stephen A
Guo, Kai
Savelieff, Masha G
Patterson, Adam
Sakowski, Stacey A
Habra, Hani
Karnovsky, Alla
Hur, Junguk
Feldman, Eva L
author_facet Goutman, Stephen A
Guo, Kai
Savelieff, Masha G
Patterson, Adam
Sakowski, Stacey A
Habra, Hani
Karnovsky, Alla
Hur, Junguk
Feldman, Eva L
author_sort Goutman, Stephen A
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease lacking effective treatments. This is due, in part, to a complex and incompletely understood pathophysiology. To shed light, we conducted untargeted metabolomics on plasma from two independent cross-sectional ALS cohorts versus control participants to identify recurrent dysregulated metabolic pathways. Untargeted metabolomics was performed on plasma from two ALS cohorts (cohort 1, n = 125; cohort 2, n = 225) and healthy controls (cohort 1, n = 71; cohort 2, n = 104). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon, adjusted logistic regression and partial least squares-discriminant analysis, while group lasso explored sub-pathway level differences. Adjustment parameters included age, sex and body mass index. Metabolomics pathway enrichment analysis was performed on metabolites selected using the above methods. Additionally, we conducted a sex sensitivity analysis due to sex imbalance in the cohort 2 control arm. Finally, a data-driven approach, differential network enrichment analysis (DNEA), was performed on a combined dataset to further identify important ALS metabolic pathways. Cohort 2 ALS participants were slightly older than the controls (64.0 versus 62.0 years, P = 0.009). Cohort 2 controls were over-represented in females (68%, P < 0.001). The most concordant cohort 1 and 2 pathways centred heavily on lipid sub-pathways, including complex and signalling lipid species and metabolic intermediates. There were differences in sub-pathways that were enriched in ALS females versus males, including in lipid sub-pathways. Finally, DNEA of the merged metabolite dataset of both ALS and control cohorts identified nine significant subnetworks; three centred on lipids and two encompassed a range of sub-pathways. In our analysis, we saw consistent and important shared metabolic sub-pathways in both ALS cohorts, particularly in lipids, further supporting their importance as ALS pathomechanisms and therapeutics targets.
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spelling pubmed-97629432022-12-20 Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts Goutman, Stephen A Guo, Kai Savelieff, Masha G Patterson, Adam Sakowski, Stacey A Habra, Hani Karnovsky, Alla Hur, Junguk Feldman, Eva L Brain Original Article Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease lacking effective treatments. This is due, in part, to a complex and incompletely understood pathophysiology. To shed light, we conducted untargeted metabolomics on plasma from two independent cross-sectional ALS cohorts versus control participants to identify recurrent dysregulated metabolic pathways. Untargeted metabolomics was performed on plasma from two ALS cohorts (cohort 1, n = 125; cohort 2, n = 225) and healthy controls (cohort 1, n = 71; cohort 2, n = 104). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon, adjusted logistic regression and partial least squares-discriminant analysis, while group lasso explored sub-pathway level differences. Adjustment parameters included age, sex and body mass index. Metabolomics pathway enrichment analysis was performed on metabolites selected using the above methods. Additionally, we conducted a sex sensitivity analysis due to sex imbalance in the cohort 2 control arm. Finally, a data-driven approach, differential network enrichment analysis (DNEA), was performed on a combined dataset to further identify important ALS metabolic pathways. Cohort 2 ALS participants were slightly older than the controls (64.0 versus 62.0 years, P = 0.009). Cohort 2 controls were over-represented in females (68%, P < 0.001). The most concordant cohort 1 and 2 pathways centred heavily on lipid sub-pathways, including complex and signalling lipid species and metabolic intermediates. There were differences in sub-pathways that were enriched in ALS females versus males, including in lipid sub-pathways. Finally, DNEA of the merged metabolite dataset of both ALS and control cohorts identified nine significant subnetworks; three centred on lipids and two encompassed a range of sub-pathways. In our analysis, we saw consistent and important shared metabolic sub-pathways in both ALS cohorts, particularly in lipids, further supporting their importance as ALS pathomechanisms and therapeutics targets. Oxford University Press 2022-01-28 /pmc/articles/PMC9762943/ /pubmed/35088843 http://dx.doi.org/10.1093/brain/awac025 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Goutman, Stephen A
Guo, Kai
Savelieff, Masha G
Patterson, Adam
Sakowski, Stacey A
Habra, Hani
Karnovsky, Alla
Hur, Junguk
Feldman, Eva L
Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts
title Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts
title_full Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts
title_fullStr Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts
title_full_unstemmed Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts
title_short Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts
title_sort metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762943/
https://www.ncbi.nlm.nih.gov/pubmed/35088843
http://dx.doi.org/10.1093/brain/awac025
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