title: Angiogenesis related genes NOS3, CD14, MMP3 and IL4R are associated to VEGF gene expression and circulating levels in healthy adults.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. The aim was to assess the genetic connections between the angiogenesis-related NOS3, CD14, MMP3, IL4R, IL4 genes and VEGF expression and plasma levels.
  
  
  METHODS
  The associations between VEGF plasma levels with the polymorphisms of NOS3, CD14, MMP3, IL4R, and IL4 were assessed in 403 healthy unrelated adults. The epistatic and environmental interactions were explored, including four VEGF-related polymorphisms previously identified. The VEGF expression in peripheral blood mononuclear cells was quantified (n = 65) for the VEGF121, VEGF145, VEGF165, and VEGF189 isoforms.
  
  
  RESULTS
  The polymorphism rs1799983 of NOS3 was associated with the sum of all VEGF isoforms mRNA levels (P = 0.032) and VEGF145 (P = 0.033). Rs1800779 of NOS3 interacted with rs3918226 of the same gene and with the rs2569190 of CD14 (P = 0.022, P = 0.042, respectively) for VEGF plasma levels. Other epistatic interactions included the rs1801275 of IL4R with the rs6921438 (VEGF-related variant) and rs3025058 of MMP3 (P = 0.042, P = 0.010 respectively) and the rs2569190 of CD14 with the rs3025058 of MMP3 (P = 0.0119). We also identified an interaction of rs1800779 with obesity, high-density lipoprotein cholesterol and triglycerides (P = 0.018, P = 0.005, P = 0.043, respectively) as well as the interaction of rs6921438 with hypertension (P = 0.028).
  
  
  CONCLUSIONS
  Our findings indicated that genetic variants of NOS3, CD14, MMP3 and IL4R are implicated in the determination of VEGF expression and plasma levels. Thus, they support the hypothesis that in physiological conditions there are complex biological relationships between pathways (such as angiogenesis and inflammation), which are involved in the development of chronic diseases.
authors.affiliation: UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio Vasculaire", Université de Lorraine, Nancy, F-54000, France. abdel.saleh@inserm.fr.
authors.forename: Abdelsalam
authors.initials: A
authors.lastname: Saleh
authors.affiliation: UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio Vasculaire", Université de Lorraine, Nancy, F-54000, France. maria.stathopoulou@inserm.fr.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Stathopoulou
authors.affiliation: UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio Vasculaire", Université de Lorraine, Nancy, F-54000, France. sebastien.dade@univ-lorraine.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dadé
authors.affiliation: UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio Vasculaire", Université de Lorraine, Nancy, F-54000, France. coumba.ndiaye@inserm.fr.
authors.forename: Ndeye Coumba
authors.initials: NC
authors.lastname: Ndiaye
authors.affiliation: UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio Vasculaire", Université de Lorraine, Nancy, F-54000, France. aziminm@gmail.com.|Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. aziminm@gmail.com.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Azimi-Nezhad
authors.affiliation: Randox Laboratories, Crumlin, UK. Helena.Murray@randox.com.
authors.forename: Helena
authors.initials: H
authors.lastname: Murray
authors.affiliation: UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio Vasculaire", Université de Lorraine, Nancy, F-54000, France. christine.masson@univ-lorraine.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Masson
authors.affiliation: Randox Laboratories, Crumlin, UK. John.Lamont@randox.com.
authors.forename: John
authors.initials: J
authors.lastname: Lamont
authors.affiliation: Randox Laboratories, Crumlin, UK. peter.fitzgerald@randox.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Fitzgerald
authors.affiliation: UMR INSERM U 1122, IGE-PCV "Interactions Gène-Environnement en Physiopathologie Cardio Vasculaire", Université de Lorraine, Nancy, F-54000, France. Sophie.Visvikis-Siest@inserm.fr.|Geriatric Service, University Hospital of Nancy, Nancy, France. Sophie.Visvikis-Siest@inserm.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
mesh_terms: D000328:Adult; D005602:France; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008137:Longitudinal Studies; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*
chemical_list: C508598:IL4 protein, human; C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; D018950:Lipopolysaccharide Receptors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015847:Interleukin-4; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3