title: Genome-wide association study for endothelial growth factors.
abstract: BACKGROUND
  Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown.
  
  
  RESULTS
  We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P=2.40×10(-65) [rs2273720] and 3.64×10(-19) [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05×10(-8) in Framingham Heart Study and 8.39×10(-5) in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P=1.84×10(-33) in Framingham Heart Study; P=2.53×10(-30) in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07×10(-8) in Framingham Heart Study; P=0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels.
  
  
  CONCLUSIONS
  Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.) wolfgang.lieb@epi.uni-kiel.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Radwan
authors.initials: R
authors.lastname: Safa
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Sebastian E
authors.initials: SE
authors.lastname: Baumeister
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Holly M
authors.initials: HM
authors.lastname: Smith
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Manja
authors.initials: M
authors.lastname: Koch
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Lorbeer
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Henri
authors.initials: H
authors.lastname: Wallaschofski
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.affiliation: From the Framingham Heart Study, MA (W.L., M.-H.C., M.G.L., H.L., R.S.V.); Christian-Albrechts-University Kiel, Institute of Epidemiology, Kiel, Germany (W.L., M.K.); Department of Neurology (M.-H.C.), Division of Graduate Medical Sciences (R.S.), Department of Medicine (H.L.), Section of Epidemiology and Prevention, School of Medicine (R.S.V.), Department of Mathematics (M.G.L.), and Department of Epidemiology, School of Public Health (R.S.V.), Boston University, MA; Interfaculty Institute for Genetics and Functional Genomics (A.T., U.V.), Section Study of Health in Pomerania - Clinical-Epidemiological Research, Institute for Community Medicine (A.T., S.E.B., R.L., H.V.), and Institute for Clinical Chemistry and Laboratory Medicine (M.N., H.W.), University Medicine, Greifswald, Germany; Cardiovascular Division, Vanderbilt University, Nashville, TN (H.M.S., D.B.S.); and German Center of Cardiovascular Research, Partner Site Greifswald, Germany (U.V., M.N., H.V., H.W.).
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
mesh_terms: D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D042787:Receptor, TIE-2 / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C066855:HGF protein, human; C555023:VPS51 protein, human; D033921:Vesicular Transport Proteins; D017228:Hepatocyte Growth Factor; D042787:Receptor, TIE-2
keywords: Genome-Wide Association Study; Tie-2 receptor; angiopoietin-2; endothelial growth factors; genetics; hepatocyte growth factor