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Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation.

Cell reports. Medicine | 2022

Effective drugs for atrial fibrillation (AF) are lacking, resulting in significant morbidity and mortality. This study demonstrates that network proximity analysis of differentially expressed genes from atrial tissue to drug targets can help prioritize repurposed drugs for AF. Using enrichment analysis of drug-gene signatures and functional testing in human inducible pluripotent stem cell (iPSC)-derived atrial-like cardiomyocytes, we identify metformin as a top repurposed drug candidate for AF. Using the active compactor, a new design analysis of large-scale longitudinal electronic health record (EHR) data, we determine that metformin use is significantly associated with a reduced risk of AF (odds ratio = 0.48, 95%, confidence interval [CI] 0.36-0.64, p < 0.001) compared with standard treatments for diabetes. This study utilizes network medicine methodologies to identify repurposed drugs for AF treatment and identifies metformin as a candidate drug.

Pubmed ID: 36223777 RIS Download

Associated grants

  • Agency: NIA NIH HHS, United States
    Id: R01 AG066707
  • Agency: NIA NIH HHS, United States
    Id: R01 AG076448
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL090620
  • Agency: NHLBI NIH HHS, United States
    Id: P01 HL158502
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL111314
  • Agency: Howard Hughes Medical Institute, United States
    Id: GT14941
  • Agency: NCRR NIH HHS, United States
    Id: UL1 RR024989
  • Agency: NIA NIH HHS, United States
    Id: U01 AG073323
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR002548
  • Agency: NHLBI NIH HHS, United States
    Id: R00 HL138272
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR001422
  • Agency: NHLBI NIH HHS, United States
    Id: K99 HL138272

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This is a list of tools and resources that we have found mentioned in this publication.


Enrichr (tool)

RRID:SCR_001575

A web-based gene list enrichment analysis tool that provides various types of visualization summaries of collective functions of gene lists. It includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes / proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries.

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ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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RRID:SCR_002309

Registry and results database of federally and privately supported clinical trials conducted in United States and around world. Provides information about purpose of trial, who may participate, locations, and phone numbers for more details. This information should be used in conjunction with advice from health care professionals.Offers information for locating federally and privately supported clinical trials for wide range of diseases and conditions. Research study in human volunteers to answer specific health questions. Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments. Observational trials address health issues in large groups of people or populations in natural settings. ClinicalTrials.gov contains trials sponsored by National Institutes of Health, other federal agencies, and private industry. Studies listed in database are conducted in all 50 States and in 178 countries.

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RRID:SCR_002700

Bioinformatics and cheminformatics database that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.

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GeneCards (tool)

RRID:SCR_002773

Database of human genes that provides concise genomic, proteomic, transcriptomic, genetic and functional information on all known and predicted human genes. Information featured in GeneCards includes orthologies, disease relationships, mutations and SNPs, gene expression, gene function, pathways, protein-protein interactions, related drugs and compounds and direct links to cutting edge research reagents and tools such as antibodies, recombinant proteins, clones, expression assays and RNAi reagents.

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RRID:SCR_003032

Software platform for complex network analysis and visualization. Used for visualization of molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles and other state data.

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Gene Set Enrichment Analysis (tool)

RRID:SCR_003199

Software package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.

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Gephi (tool)

RRID:SCR_004293

Open-source software for network visualization and analysis helping data analysts to intuitively reveal patterns and trends, highlight outliers and tells stories with their data. It uses a 3D render engine to display large graphs in real-time and to speed up the exploration. Gephi combines built-in functionalities and flexible architecture to: explore, analyze, spatialize, filter, cluterize, manipulate and export all types of networks. Gephi runs on Windows, Linux and Mac OS X. Gephi is based on a visualize-and-manipulate paradigm which allow any user to discover networks and data properties. Moreover, it is designed to follow the chain of a case study, from data file to nice printable maps. It is open-source and free (GNU General Public License). Applications: * Exploratory Data Analysis: intuition-oriented analysis by networks manipulations in real time. * Link Analysis: revealing the underlying structures of associations between objects, in particular in scale-free networks. * Social Network Analysis: easy creation of social data connectors to map community organizations and small-world networks. * Biological Network analysis: representing patterns of biological data. * Poster creation: scientific work promotion with hi-quality printable maps. Gephi 0.7 architecture is modular and therefore allows developers to add and extend functionalities with ease. New features like Metrics, Layout, Filters, Data sources and more can be easily packaged in plugins and shared. The built-in Plugins Center automatically gets the list of plugins available from the Gephi Plugin portal and takes care of all software updates. Download, comment, and rate plugins provided by community members and third-party companies, or post your own contributions!

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UniProtKB (tool)

RRID:SCR_004426

Central repository for collection of functional information on proteins, with accurate and consistent annotation. In addition to capturing core data mandatory for each UniProtKB entry (mainly, the amino acid sequence, protein name or description, taxonomic data and citation information), as much annotation information as possible is added. This includes widely accepted biological ontologies, classifications and cross-references, and experimental and computational data. The UniProt Knowledgebase consists of two sections, UniProtKB/Swiss-Prot and UniProtKB/TrEMBL. UniProtKB/Swiss-Prot (reviewed) is a high quality manually annotated and non-redundant protein sequence database which brings together experimental results, computed features, and scientific conclusions. UniProtKB/TrEMBL (unreviewed) contains protein sequences associated with computationally generated annotation and large-scale functional characterization that await full manual annotation. Users may browse by taxonomy, keyword, gene ontology, enzyme class or pathway.

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Gene Expression Omnibus (GEO) (tool)

RRID:SCR_005012

Functional genomics data repository supporting MIAME-compliant data submissions. Includes microarray-based experiments measuring the abundance of mRNA, genomic DNA, and protein molecules, as well as non-array-based technologies such as serial analysis of gene expression (SAGE) and mass spectrometry proteomic technology. Array- and sequence-based data are accepted. Collection of curated gene expression DataSets, as well as original Series and Platform records. The database can be searched using keywords, organism, DataSet type and authors. DataSet records contain additional resources including cluster tools and differential expression queries.

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Picard (tool)

RRID:SCR_006525

Java toolset for working with next generation sequencing data in the BAM format.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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LIMMA (tool)

RRID:SCR_010943

Software package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.

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KEGG (tool)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

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RRID:SCR_013035

Software tool for fast and high throughput alignment of shotgun cDNA sequencing reads generated by transcriptomics technologies. Fast splice junction mapper for RNA-Seq reads. Aligns RNA-Seq reads to mammalian-sized genomes using ultra high-throughput short read aligner Bowtie, and then analyzes mapping results to identify splice junctions between exons.TopHat2 is accurate alignment of transcriptomes in presence of insertions, deletions and gene fusions.

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RRID:SCR_013651

An Antibody supplier

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RRID:SCR_014966

Human and mouse genome annotation project which aims to identify all gene features in the human genome using computational analysis, manual annotation, and experimental validation.

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Biorender (tool)

RRID:SCR_018361

Web tool for graphical illustrations for biological systems by BioRender. Used for articles and presentations. Collection of pre made icons and templates from life science fields for scientific illustrations. Customized icons possible on request.

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MCF-7 (tool)

RRID:CVCL_0031

Cell line MCF-7 is a Cancer cell line with a species of origin Homo sapiens (Human)

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