title: Shared molecular pathways and gene networks for cardiovascular disease and type 2 diabetes mellitus in women across diverse ethnicities.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Kei Hang K
authors.initials: KH
authors.lastname: Chan
authors.affiliation: 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.).
authors.forename: Yen-Tsung
authors.initials: YT
authors.lastname: Huang
authors.affiliation: 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.).
authors.forename: Qingying
authors.initials: Q
authors.lastname: Meng
authors.affiliation: 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.).
authors.forename: Chunyuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Reiner
authors.affiliation: 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.).
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sobel
authors.affiliation: 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.).
authors.forename: Lesley
authors.initials: L
authors.lastname: Tinker
authors.affiliation: 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.).
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: 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.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Simin
authors.initials: S
authors.lastname: Liu
mesh_terms: D000368:Aged; D044383:Black People / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D004549:Elastin / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D004549:Elastin
keywords: cardiovascular diseases; diabetes mellitus; ethnology; genetics; genome-wide association study; women