Functional Role of the L396R Mutation of Tks5 Identified by an Exome-Wide Association Study in Atrial Fibrillation

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  • Yang Xiaoxi
    Department of Bio-information Pharmacology, Medical Research Institute, Tokyo Medical and Dental University Department of Cardiovascular Medicine, The First Hospital of China Medical University
  • Sasano Tetsuo
    Department of Biofunctional Informatics, Graduate School of Medicine, Tokyo Medical and Dental University Department of Cardiovascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University
  • Ebana Yusuke
    Department of Bio-information Pharmacology, Medical Research Institute, Tokyo Medical and Dental University Life Science and Bioethics Research Center, Tokyo Medical and Dental Science
  • Takeuchi Jun K.
    Department of Bio-information Pharmacology, Medical Research Institute, Tokyo Medical and Dental University
  • Ihara Kensuke
    Department of Bio-information Pharmacology, Medical Research Institute, Tokyo Medical and Dental University
  • Yamazoe Masahiro
    Department of Bio-information Pharmacology, Medical Research Institute, Tokyo Medical and Dental University Department of Biofunctional Informatics, Graduate School of Medicine, Tokyo Medical and Dental University
  • Furukawa Tetsushi
    Department of Bio-information Pharmacology, Medical Research Institute, Tokyo Medical and Dental University

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Abstract

<p>Background:Atrial fibrillation (AF) is the most common cardiac arrhythmia; however, the current treatment strategies for AF have limited efficacy. Thus, a better understanding of the mechanisms underlying AF is important for future therapeutic strategy. A previous study (Exome-Wide Association Study (ExWAS)) identified a rare variant, rs202011870 (MAF=0.00036, GenomAD), which is highly associated with AF (OR=3.617, P<0.0001). rs202011870 results in the replacement of Leu at 396 with Arg (L396R) in a molecule, Tks5; however, the mechanism of how rs202011870 links to AF is completely unknown.</p><p>Methods and Results:The association of rs202011870 with AF was examined in 3,378 participants (641 control and 2,737 AF cases) from 4 independent cohorts by using an Invader assay. Consequences of rs202011870 in migration ability, podosome formation, and expression of inflammation-related molecules in macrophages were examined using RAW264.7 cells with a trans-well assay, immunocytochemistry, and qPCR assay. Validation of the association of rs202011870 with AF was successful. In vitro studies showed that RAW264.7 cells with L396R-Tks5 increased trans-well migration ability, and enhanced podosome formation. RAW264.7 cells with L396R-Tks5 also increased the expression of several inflammatory cytokines and inflammation-related molecules.</p><p>Conclusions:L396R mutation in Tks5 associated with AF enhances migration of macrophages and their inflammatory features, resulting in enhanced susceptibility to AF.</p>

Journal

  • Circulation Journal

    Circulation Journal 84 (12), 2148-2157, 2020-11-25

    The Japanese Circulation Society

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