A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson's disease.
1. BMC Med Genomics. 2017 Sep 19;10(1):56. doi: 10.1186/s12920-017-0291-0. A systematic review and integrative approach to decode the common molecular link between levodopa response and Parkinson's disease. Guin D(1), Mishra MK(1)(2), Talwar P(1), Rawat C(1)(3), Kushwaha SS(4), Kukreti S(2), Kukreti R(5)(6). Author information: (1)Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, New Delhi, -110007, India. (2)Department of Chemistry, Nucleic Acids Research Lab, University of Delhi (North Campus), Delhi, India. (3)Academy of Scientific & Innovative Research (AcSIR), CSIR- Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, New Delhi, India. (4)Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi, India. (5)Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, New Delhi, -110007, India. ritus@igib.res.in. (6)Academy of Scientific & Innovative Research (AcSIR), CSIR- Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, New Delhi, India. ritus@igib.res.in. 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, CAn 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. DOI: 10.1186/s12920-017-0291-0 PMCID: PMC5606117 PMID: 28927418 [Indexed for MEDLINE] Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: No patient samples were collected and analysed during this study. All GWAS data were provided as summary statistics by the consortia acknowledged in this study having been collected in accordance with ethical regulations in the partner countries and as defined in original research publications by such consortia. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare no potential conflict of interest. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
