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

Jessica C Lal; Chengsheng Mao; Yadi Zhou; Shamone R Gore-Panter; Julie H Rennison; Beth S Lovano; Laurie Castel; Jiyoung Shin; A Marc Gillinov; Jonathan D Smith; John Barnard; David R Van Wagoner; Yuan Luo; Feixiong Cheng; Mina K Chung

doi:10.1016/j.xcrm.2022.100749

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

Cell Rep Med. 2022 Oct 18;3(10):100749. doi: 10.1016/j.xcrm.2022.100749. Epub 2022 Oct 11.

Authors

Affiliations

¹ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., NE5-305, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
² Division of Health and Biomedical Informatics, Department of Preventive Medicine, Northwestern University, Chicago, IL 60611, USA.
³ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., NE5-305, Cleveland, OH 44195, USA.
⁴ Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA.
⁵ Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶ Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH 44195, USA.
⁷ Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁸ Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
⁹ Division of Health and Biomedical Informatics, Department of Preventive Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: yuan.luo@northwestern.edu.
¹⁰ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., NE5-305, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: chengf@ccf.org.
¹¹ Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, 9500 Euclid Ave., J2-2, OH 44195, USA. Electronic address: chungm@ccf.org.

Abstract

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.

Keywords: EHR; atrial fibrillation; drug repurposing; electronic health record; human inducible pluripotent stem cells; network medicine; pharmacoepidemiology; systems biology.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Atrial Fibrillation* / drug therapy
Heart Atria
Humans
Metformin* / pharmacology
Transcriptome

Substances

Metformin

Abstract

Publication types

MeSH terms

Substances

Grants and funding