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Biological Pathways and Gene Networks Link Inflammation and Vascular Remodeling to Both Heart Failure with Preserved and Reduced Ejection Fraction in Women across Ethnicities

View ORCID ProfileQing Liu, Kei Hang K. Chan, Alan R. Morrison, Stephen T. McGarvey, Xi Luo, James G. Wilson, Adolfo Correa, Alexander P. Reiner, Jie Li, Simin Liu, Wen-Chih Wu
doi: https://doi.org/10.1101/726208
Qing Liu
1Department of Epidemiology, School of Public Health, Brown University, Providence, RI 02912, USA
2Center for Global Cardiometabolic Health, Brown University, 121 South Main St, Providence, RI, 02903
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  • ORCID record for Qing Liu
Kei Hang K. Chan
2Center for Global Cardiometabolic Health, Brown University, 121 South Main St, Providence, RI, 02903
3Department of Biomedical Sciences, City University of Hong Kong, Hong Kong
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Alan R. Morrison
4Providence Veterans Affairs Medical Center, Providence, RI 02908, USA
5Alpert Medical School at Brown University, Providence, RI 02903, USA
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Stephen T. McGarvey
1Department of Epidemiology, School of Public Health, Brown University, Providence, RI 02912, USA
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Xi Luo
6Department of Biostatistics and Data Science, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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James G. Wilson
7Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216
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Adolfo Correa
8Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216
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Alexander P. Reiner
9Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
10Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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Jie Li
1Department of Epidemiology, School of Public Health, Brown University, Providence, RI 02912, USA
2Center for Global Cardiometabolic Health, Brown University, 121 South Main St, Providence, RI, 02903
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Simin Liu
1Department of Epidemiology, School of Public Health, Brown University, Providence, RI 02912, USA
2Center for Global Cardiometabolic Health, Brown University, 121 South Main St, Providence, RI, 02903
5Alpert Medical School at Brown University, Providence, RI 02903, USA
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  • For correspondence: simin_liu@brown.edu Wen-Chih.Wu@va.gov
Wen-Chih Wu
1Department of Epidemiology, School of Public Health, Brown University, Providence, RI 02912, USA
4Providence Veterans Affairs Medical Center, Providence, RI 02908, USA
5Alpert Medical School at Brown University, Providence, RI 02903, USA
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  • For correspondence: simin_liu@brown.edu Wen-Chih.Wu@va.gov
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Abstract

Introduction Heart failure (HF) is understudied among women; especially, genomic evidence implicating shared or unique mechanisms of HF with respect to reduced or preserved ejection fraction (HFrEF, HFpEF) is lacking across ethnic populations of women. Prior genome-wide association studies (GWAS) have identified approximately 30 suggestive genetic variants for HF, although none have been specifically linked to HFrEF or HFpEF.

Objectives We aimed to define, replicate, and annotate genetic variants to HFrEF, HFpEF, or both, as well as to investigate potential biological mechanisms underlying HFrEF and HFpEF among African American (AA) and European American (EA) women in three well-characterized, high-quality prospective cohorts, the Women’s Health Initiative (WHI) study, the Jackson Heart Study (JHS), and the Framingham Heart Study (FHS).

Methods GWAS analysis on HFrEF and HFpEF were first performed among 7,982 AA and 4,133 EA in the WHI, followed by pathway analysis employing two independent methodological platforms (GSA-SNP and Mergeomics) curating KEGG, Reactome, and BioCarta pathway databases. GWAS signals and biological pathways identified using the WHI were replicated in the JHS and FHS. For all replicated pathways, we performed cross-phenotype and cross-ethnicity validation analyses to examine shared pathways between HFrEF and HFpEF, and phenotype-specific pathways, across ethnicities. We further prioritized key driver genes for HF according to specific pathways identified.

Results We validated one previously reported genetic locus and identified six new ones, among which one locus was allocated to HFrEF and five to HFpEF. Additionally, we defined five biological pathways shared between HFrEF and HFpEF and discovered six HFpEF-specific pathways. These pathways overlapped in two main domains for molecular signaling: 1) inflammation and 2) vascular remodeling (including angiogenesis and vascular patterning), involving key driver genes from collagen and HLA gene families.

Conclusions Our network analysis of three large prospective cohorts of women in the United States defined several novel loci for HF and its subtypes. In particular, several key driver genes reinforce the mechanistic role of inflammation and vascular remodeling in the development of HF, especially HFpEF. Given that therapeutic strategies developed for left ventricular dysfunction have had limited success for HFpEF, several new targets and pathways identified and validated in this study should be further assessed in risk stratification as well as the design of potential new HF interventions.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 06, 2019.
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Biological Pathways and Gene Networks Link Inflammation and Vascular Remodeling to Both Heart Failure with Preserved and Reduced Ejection Fraction in Women across Ethnicities
Qing Liu, Kei Hang K. Chan, Alan R. Morrison, Stephen T. McGarvey, Xi Luo, James G. Wilson, Adolfo Correa, Alexander P. Reiner, Jie Li, Simin Liu, Wen-Chih Wu
bioRxiv 726208; doi: https://doi.org/10.1101/726208
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Biological Pathways and Gene Networks Link Inflammation and Vascular Remodeling to Both Heart Failure with Preserved and Reduced Ejection Fraction in Women across Ethnicities
Qing Liu, Kei Hang K. Chan, Alan R. Morrison, Stephen T. McGarvey, Xi Luo, James G. Wilson, Adolfo Correa, Alexander P. Reiner, Jie Li, Simin Liu, Wen-Chih Wu
bioRxiv 726208; doi: https://doi.org/10.1101/726208

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