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PLoS Genet. 2017 Sep 28;13(9):e1007040. doi: 10.1371/journal.pgen.1007040. eCollection 2017 Sep.

Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.

Author information

1
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, United States of America.
2
Departments of Epidemiology and Medicine and Center for Global Cardiometabolic Health, Brown University, Providence, RI, United States of America.
3
Hong Kong Institute of Diabetes and Obesity, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.
4
The Framingham Heart Study, Framingham, MA, USA and the Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, United States of America.
5
Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.
6
ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
7
Department of Public Health, Hangzhou Normal University School of Medicine, Hangzhou, China.
8
Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
9
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States of America.
10
Department of Biostatistics, Brown University, Providence, RI, United States of America.
11
Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States of America.
12
Department of Endocrinology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
13
Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, United States of America.
14
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, United States of America.

Abstract

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.

PMID:
28957322
PMCID:
PMC5634657
DOI:
10.1371/journal.pgen.1007040
[Indexed for MEDLINE]
Free PMC Article

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