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Genetic architecture of heart failure with preserved versus reduced ejection fraction

Author

Listed:
  • Jacob Joseph

    (VA Boston Healthcare System
    Brigham and Women’s Hospital, Harvard Medical School
    VA Providence Healthcare System)

  • Chang Liu

    (Emory University Rollins School of Public Health)

  • Qin Hui

    (Emory University Rollins School of Public Health
    Atlanta VA Health Care System)

  • Krishna Aragam

    (VA Boston Healthcare System
    Massachusetts General Hospital
    Broad Institute of Harvard and MIT)

  • Zeyuan Wang

    (Emory University Rollins School of Public Health
    Atlanta VA Health Care System)

  • Brian Charest

    (VA Boston Healthcare System)

  • Jennifer E. Huffman

    (VA Boston Healthcare System)

  • Jacob M. Keaton

    (National Institutes of Health
    Vanderbilt University Medical Center)

  • Todd L. Edwards

    (Vanderbilt University Medical Center)

  • Serkalem Demissie

    (VA Boston Healthcare System
    Boston University School of Medicine)

  • Luc Djousse

    (VA Boston Healthcare System
    Brigham and Women’s Hospital, Harvard Medical School)

  • Juan P. Casas

    (VA Boston Healthcare System
    Brigham and Women’s Hospital, Harvard Medical School)

  • J. Michael Gaziano

    (VA Boston Healthcare System
    Brigham and Women’s Hospital, Harvard Medical School)

  • Kelly Cho

    (VA Boston Healthcare System
    Brigham and Women’s Hospital, Harvard Medical School)

  • Peter W. F. Wilson

    (Atlanta VA Health Care System
    Emory University School of Medicine)

  • Lawrence S. Phillips

    (Atlanta VA Health Care System
    Emory University School of Medicine)

  • Christopher J. O’Donnell

    (VA Boston Healthcare System
    Brigham and Women’s Hospital, Harvard Medical School)

  • Yan V. Sun

    (Emory University Rollins School of Public Health
    Atlanta VA Health Care System)

Abstract

Pharmacologic clinical trials for heart failure with preserved ejection fraction have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction. Whether differences in the genetic underpinnings of these major heart failure subtypes may provide insights into the disparate outcomes of clinical trials remains unknown. We utilize a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced and with preserved ejection fractions based on current clinical definitions, to conduct detailed genetic analyses of the two heart failure sub-types. We find different genetic architectures and distinct genetic association profiles between heart failure with reduced and with preserved ejection fraction suggesting differences in underlying pathobiology. The modest genetic discovery for heart failure with preserved ejection fraction (one locus) compared to heart failure with reduced ejection fraction (13 loci) despite comparable sample sizes indicates that clinically defined heart failure with preserved ejection fraction likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of heart failure with preserved ejection fraction is paramount to better dissect the underlying genetic signals and contributors to this highly prevalent condition.

Suggested Citation

  • Jacob Joseph & Chang Liu & Qin Hui & Krishna Aragam & Zeyuan Wang & Brian Charest & Jennifer E. Huffman & Jacob M. Keaton & Todd L. Edwards & Serkalem Demissie & Luc Djousse & Juan P. Casas & J. Micha, 2022. "Genetic architecture of heart failure with preserved versus reduced ejection fraction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35323-0
    DOI: 10.1038/s41467-022-35323-0
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    1. Danielle Rasooly & Gina M. Peloso & Alexandre C. Pereira & Hesam Dashti & Claudia Giambartolomei & Eleanor Wheeler & Nay Aung & Brian R. Ferolito & Maik Pietzner & Eric H. Farber-Eger & Quinn Stanton , 2023. "Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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