Article (Scientific journals)
Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.
Shu, Le; Chan, Kei Hang K.; Zhang, Guanglin et al.
2017In PLoS Genetics, 13 (9), p. 1007040
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Keywords :
Adipocytes/metabolism; Amino Acids, Branched-Chain/metabolism; Animals; Cardiovascular Diseases/genetics; Caveolin 1/genetics/metabolism; Diabetes Mellitus, Type 2/genetics; Disease Models, Animal; Ethnicity/genetics; Extracellular Matrix Proteins/genetics/metabolism; Gene Expression Regulation; Gene Regulatory Networks; Genome-Wide Association Study; Glucose/metabolism; Glycoproteins/genetics/metabolism; Humans; Hydroxymethylglutaryl CoA Reductases/genetics/metabolism; Insulin-Like Growth Factor I/genetics/metabolism; Lipid Metabolism; Male; Mice; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Reproducibility of Results; United States
Abstract :
[en] Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are closely interrelated complex diseases likely sharing overlapping pathogenesis driven by aberrant activities in gene networks. However, the molecular circuitries underlying the pathogenic commonalities remain poorly understood. We sought to identify the shared gene networks and their key intervening drivers for both CVD and T2D by conducting a comprehensive integrative analysis driven by five multi-ethnic genome-wide association studies (GWAS) for CVD and T2D, expression quantitative trait loci (eQTLs), ENCODE, and tissue-specific gene network models (both co-expression and graphical models) from CVD and T2D relevant tissues. We identified pathways regulating the metabolism of lipids, glucose, and branched-chain amino acids, along with those governing oxidation, extracellular matrix, immune response, and neuronal system as shared pathogenic processes for both diseases. Further, we uncovered 15 key drivers including HMGCR, CAV1, IGF1 and PCOLCE, whose network neighbors collectively account for approximately 35% of known GWAS hits for CVD and 22% for T2D. Finally, we cross-validated the regulatory role of the top key drivers using in vitro siRNA knockdown, in vivo gene knockout, and two Hybrid Mouse Diversity Panels each comprised of >100 strains. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide strong support that common sets of tissue-specific molecular networks drive the pathogenesis of both CVD and T2D across ethnicities and help prioritize new therapeutic avenues for both CVD and T2D.
Disciplines :
Genetics & genetic processes
Author, co-author :
Shu, Le
Chan, Kei Hang K.
Zhang, Guanglin
Huan, Tianxiao
Kurt, Zeyneb
Zhao, Yuqi
Codoni, Veronica  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core ; Institut National de la Santé et de la Recherche Médicale - INSERM > Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1166
Trégouët, David-Alexandre
Yang, Jun
Wilson, James G.
Luo, Xi
Levy, Daniel
Lusis, Aldons J.
Liu, Simin
Yang, Xia
More authors (5 more) Less
External co-authors :
yes
Language :
English
Title :
Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.
Publication date :
2017
Journal title :
PLoS Genetics
ISSN :
1553-7404
Publisher :
Public Library of Science, United States - California
Volume :
13
Issue :
9
Pages :
e1007040
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 19 December 2022

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