Genetic architecture of heart failure with preserved versus reduced ejection fraction

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. Michael Gaziano, Kelly Cho, Peter W. F. Wilson, Lawrence S. Phillips, Christopher J. O’Donnell and Yan V. Sun ()
Additional contact information
Jacob Joseph: VA Boston Healthcare System
Chang Liu: Emory University Rollins School of Public Health
Qin Hui: Emory University Rollins School of Public Health
Krishna Aragam: VA Boston Healthcare System
Zeyuan Wang: Emory University Rollins School of Public Health
Brian Charest: VA Boston Healthcare System
Jennifer E. Huffman: VA Boston Healthcare System
Jacob M. Keaton: National Institutes of Health
Todd L. Edwards: Vanderbilt University Medical Center
Serkalem Demissie: VA Boston Healthcare System
Luc Djousse: VA Boston Healthcare System
Juan P. Casas: VA Boston Healthcare System
J. Michael Gaziano: VA Boston Healthcare System
Kelly Cho: VA Boston Healthcare System
Peter W. F. Wilson: Atlanta VA Health Care System
Lawrence S. Phillips: Atlanta VA Health Care System
Christopher J. O’Donnell: VA Boston Healthcare System
Yan V. Sun: Emory University Rollins School of Public Health

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35323-0

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