Kei Hang K Chan1, Yen-Tsung Huang1, Qingying Meng1, Chunyuan Wu1, Alexander Reiner1, Eric M Sobel1, Lesley Tinker1, Aldons J Lusis1, Xia Yang2, Simin Liu2. 1. From the Department of Epidemiology (K.H.K.C., Y.-T.H., S.L.) and Division of Endocrinology, Department of Medicine (S.L.), Warren Alpert Medical School of Brown University, Providence, RI; Department of Integrative Biology and Physiology (K.H.K.C., Q.M., X.Y.), Department of Human Genetics (E.M.S.), Department of Medicine/Division of Cardiology, David Geffen School of Medicine (A.J.L.), and Departments of Medicine and Obstetrics and Gynecology, David Geffen School of Medicine (S.L.), University of California Los Angeles; Biostatistics Division (C.W.), Public Health Sciences Division (L.T.), Fred Hutchinson Cancer Research Center, Seattle, WA; and Department of Epidemiology, University of Washington, Seattle (A.R.). 2. From the Department of Epidemiology (K.H.K.C., Y.-T.H., S.L.) and Division of Endocrinology, Department of Medicine (S.L.), Warren Alpert Medical School of Brown University, Providence, RI; Department of Integrative Biology and Physiology (K.H.K.C., Q.M., X.Y.), Department of Human Genetics (E.M.S.), Department of Medicine/Division of Cardiology, David Geffen School of Medicine (A.J.L.), and Departments of Medicine and Obstetrics and Gynecology, David Geffen School of Medicine (S.L.), University of California Los Angeles; Biostatistics Division (C.W.), Public Health Sciences Division (L.T.), Fred Hutchinson Cancer Research Center, Seattle, WA; and Department of Epidemiology, University of Washington, Seattle (A.R.). xyang123@ucla.edu simin_liu@brown.edu.
Abstract
BACKGROUND: Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. METHODS AND RESULTS: Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. CONCLUSIONS: Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.
BACKGROUND: Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. METHODS AND RESULTS: Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. CONCLUSIONS: Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.
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