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A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease

BACKGROUND: PD is a progressive neurodegenerative disorder commonly treated by levodopa. The findings from genetic studies on adverse effects (ADRs) and levodopa efficacy are mostly inconclusive. Here, we aim to identify predictive genetic biomarkers for levodopa response (LR) and determine common m...

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Autores principales: Guin, Debleena, Mishra, Manish Kumar, Talwar, Puneet, Rawat, Chitra, Kushwaha, Suman S., Kukreti, Shrikant, Kukreti, Ritushree
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606117/
https://www.ncbi.nlm.nih.gov/pubmed/28927418
http://dx.doi.org/10.1186/s12920-017-0291-0
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author Guin, Debleena
Mishra, Manish Kumar
Talwar, Puneet
Rawat, Chitra
Kushwaha, Suman S.
Kukreti, Shrikant
Kukreti, Ritushree
author_facet Guin, Debleena
Mishra, Manish Kumar
Talwar, Puneet
Rawat, Chitra
Kushwaha, Suman S.
Kukreti, Shrikant
Kukreti, Ritushree
author_sort Guin, Debleena
collection PubMed
description BACKGROUND: PD is a progressive neurodegenerative disorder commonly treated by levodopa. The findings from genetic studies on adverse effects (ADRs) and levodopa efficacy are mostly inconclusive. Here, we aim to identify predictive genetic biomarkers for levodopa response (LR) and determine common molecular link with disease susceptibility. A systematic review for LR was conducted for ADR, and drug efficacy, independently. All included articles were assessed for methodological quality on 14 parameters. GWAS of PD were also reviewed. Protein-protein interaction (PPI) analysis using STRING and functional enrichment using WebGestalt was performed to explore the common link between LR and PD. RESULTS: From 37 candidate studies on levodopa toxicity, 18 genes were found associated, of which, CA(n) STR 13, 14 (DRD2) was most significantly associated with dyskinesia, followed by rs1801133 (MTHFR) with hyper-homocysteinemia, and rs474559 (HOMER1) with hallucination. Similarly, 8 studies on efficacy resulted in 4 genes in which rs28363170, rs3836790 (SLC6A3) and rs4680 (COMT), were significant. To establish the molecular connection between LR with PD, we identified 35 genes significantly associated with PD. With 19 proteins associated with LR and 35 with PD, two independent PPI networks were constructed. Among the 67 nodes (263 edges) in LR, and 62 nodes (190 edges) in PD pathophysiology, UBC, SNCA, FYN, SRC, CAMK2A, and SLC6A3 were identified as common potential candidates. CONCLUSION: Our study revealed the genetically significant polymorphism concerning the ADRs and levodopa efficacy. The six common genes may be used as predictive markers for therapy optimization and as putative drug target candidates. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12920-017-0291-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-56061172017-09-20 A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease Guin, Debleena Mishra, Manish Kumar Talwar, Puneet Rawat, Chitra Kushwaha, Suman S. Kukreti, Shrikant Kukreti, Ritushree BMC Med Genomics Research Article BACKGROUND: PD is a progressive neurodegenerative disorder commonly treated by levodopa. The findings from genetic studies on adverse effects (ADRs) and levodopa efficacy are mostly inconclusive. Here, we aim to identify predictive genetic biomarkers for levodopa response (LR) and determine common molecular link with disease susceptibility. A systematic review for LR was conducted for ADR, and drug efficacy, independently. All included articles were assessed for methodological quality on 14 parameters. GWAS of PD were also reviewed. Protein-protein interaction (PPI) analysis using STRING and functional enrichment using WebGestalt was performed to explore the common link between LR and PD. RESULTS: From 37 candidate studies on levodopa toxicity, 18 genes were found associated, of which, CA(n) STR 13, 14 (DRD2) was most significantly associated with dyskinesia, followed by rs1801133 (MTHFR) with hyper-homocysteinemia, and rs474559 (HOMER1) with hallucination. Similarly, 8 studies on efficacy resulted in 4 genes in which rs28363170, rs3836790 (SLC6A3) and rs4680 (COMT), were significant. To establish the molecular connection between LR with PD, we identified 35 genes significantly associated with PD. With 19 proteins associated with LR and 35 with PD, two independent PPI networks were constructed. Among the 67 nodes (263 edges) in LR, and 62 nodes (190 edges) in PD pathophysiology, UBC, SNCA, FYN, SRC, CAMK2A, and SLC6A3 were identified as common potential candidates. CONCLUSION: Our study revealed the genetically significant polymorphism concerning the ADRs and levodopa efficacy. The six common genes may be used as predictive markers for therapy optimization and as putative drug target candidates. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12920-017-0291-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-09-19 /pmc/articles/PMC5606117/ /pubmed/28927418 http://dx.doi.org/10.1186/s12920-017-0291-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Guin, Debleena
Mishra, Manish Kumar
Talwar, Puneet
Rawat, Chitra
Kushwaha, Suman S.
Kukreti, Shrikant
Kukreti, Ritushree
A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease
title A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease
title_full A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease
title_fullStr A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease
title_full_unstemmed A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease
title_short A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson’s disease
title_sort systematic review and integrative approach to decode the common molecular link between levodopa response and parkinson’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606117/
https://www.ncbi.nlm.nih.gov/pubmed/28927418
http://dx.doi.org/10.1186/s12920-017-0291-0
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