title: Serum Angiopoietin-Like Protein 2 Is a Novel Risk Factor for Cardiovascular Disease in the Community: The Hisayama Study.
abstract: Angiopoietin-like protein 2 (ANGPTL2), a proinflammatory mediator, has been reported to accelerate the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. However, no cohort studies have examined the relationship between serum ANGPTL2 levels and the development of cardiovascular disease (CVD) in a general population.
  
  
  
  A total of 3005 community-dwelling Japanese aged ≥40 years without a history of CVD were divided into 4 groups according to the quartiles of serum ANGPTL2 concentrations (Q1, lowest and Q4, highest) and followed up for 10 years. The hazards ratios and their 95% confidence intervals for the development of CVD (coronary heart disease or stroke) were estimated using a Cox proportional hazards model. During the follow-up, 219 first-ever CVD events were observed. The risk of CVD increased significantly with elevating ANGPTL2 levels after adjustment for age, sex, serum total cholesterol, use of lipid-lowering agents, ECG abnormalities, smoking habits, alcohol intake, and regular exercise (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.27 [0.80-2.04]; Q3, 1.48 [0.95-2.32]; and Q4, 1.85 [1.20-2.85]; P=0.003 for trend). After additional adjustment for metabolic syndrome components and serum high-sensitivity C-reactive protein levels as an inflammatory marker, the association was attenuated but remained significant (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.21 [0.76-1.94]; Q3, 1.38 [0.87-2.17]; and Q4, 1.66 [1.05-2.60]; P=0.02 for trend).
  
  
  
  Our findings suggest that elevated serum ANGPTL2 levels are a novel risk factor for the development of CVD in the general population. This association is partially mediated by metabolic disorders and inflammation.
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.). junhata@cohort.med.kyushu-u.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Hata
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Naoko
authors.initials: N
authors.lastname: Mukai
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nagata
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohara
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Daigo
authors.initials: D
authors.lastname: Yoshida
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Hiro
authors.initials: H
authors.lastname: Kishimoto
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Mao
authors.initials: M
authors.lastname: Shibata
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hirakawa
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ago
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kiyohara
authors.affiliation: From the Center for Cohort Studies (J.H., N.M, D.Y., T.K., Y.K., T.N.), Departments of Environmental Medicine (J.H., N.M., M.N., T.O., D.Y., H.K., M.S., Y.H., Y.K.), Medicine and Clinical Science (J.H., N.M., M.N., Y.H., T.A., T.K.), Neuropsychiatry (T.O.), and Psychosomatic Medicine (M.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan (M.E., Y.O.).
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ninomiya
mesh_terms: D017677:Age Distribution; D000368:Aged; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology*; D005260:Female; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000097:blood / Q000453:epidemiology; D007564:Japan / Q000453:epidemiology; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008659:Metabolic Diseases / Q000097:blood / Q000453:epidemiology; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D017678:Sex Distribution; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C485792:ANGPTL2 protein, human; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D015415:Biomarkers; D002097:C-Reactive Protein
keywords: angiopoietin; cardiovascular disease; cohort study; inflammation; stroke