title: Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study.
abstract: BACKGROUND
  Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases.
  
  
  RESULTS
  We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection index and stiffness index). In a subsample of 1372 individuals, ADM gene expression was assessed as part of a transcriptomic study of circulating monocytes. Nongenetic factors explained 45.8% and 7.5% of MR-pro-ADM and ADM expression variability, respectively. ADM expression correlated with plasma C-reactive protein, interleukin-receptor 1A, and myeloperoxidase, whereas MR-pro-ADM levels correlated with C-terminal proendothelin-1, creatinine, and N-terminal pro-B-type natriuretic peptide. Genome-wide association study of ADM expression and MR-pro-ADM levels both identified a single locus encompassing the ADM gene. ADM expression was associated with 1 single nucleotide polymorphism rs11042717 (P=2.36×10(-12)), whereas MR-pro-ADM was associated with 2 single nucleotide polymorphisms with additive effects, rs2957692 (P=1.54×10(-13)) and rs2957717 (P=4.24×10(-8)). Reflection index was independently associated with rs11042717 (P<10(-4)) and ADM expression (P=0.0002) but not with MR-pro-ADM. Weaker associations were observed for stiffness index. Intima-media thickness was not related to ADM single nucleotide polymorphisms or expression.
  
  
  CONCLUSIONS
  These results support an involvement of the ADM gene in the modulation of peripheral vascular tone.
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Farzin
authors: F
authors: Beygui
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Philipp S
authors: PS
authors: Wild
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Tanja
authors: T
authors: Zeller
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Marine
authors: M
authors: Germain
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Raphaele
authors: R
authors: Castagné
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Karl J
authors: KJ
authors: Lackner
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Thomas
authors: T
authors: Münzel
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Gilles
authors: G
authors: Montalescot
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Gary F
authors: GF
authors: Mitchell
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Germaine C
authors: GC
authors: Verwoert
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: Kirill V
authors: KV
authors: Tarasov
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: David-Alexandre
authors: DA
authors: Trégouët
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.).
authors: François
authors: F
authors: Cambien
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.). laurence.tiret@upmc.fr s.blankenberg@uke.de.
authors: Stefan
authors: S
authors: Blankenberg
authors: From UMR_S 1166, Sorbonne Universités UPMC Université Paris 06, UMR_S 1166 INSERM, UMR_S 1166 ICAN Institute for Cardiometabolism and Nutrition, Paris, France (F.B., M.G., R.C., G.M., D.-A.T., F.C., L.T.); Department of Cardiology, Caen University Hospital, Caen, France (F.B.); Department of Medicine II (P.S.W., T.M.), Center for Thrombosis and Hemostasis (P.S.W.), Institute for Clinical Chemistry and Laboratory Medicine (K.J.L.), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany (T.Z., S.B.); Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Group, AP-HP, Université Paris 6), Paris, France (G.M.); Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (G.C.V.); and Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD (K.V.T.). laurence.tiret@upmc.fr s.blankenberg@uke.de.
authors: Laurence
authors: L
authors: Tiret
mesh_terms: D053607:Adrenomedullin / Q000097:blood* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D059168:Carotid Intima-Media Thickness; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D020641:Polymorphism, Single Nucleotide; D011498:Protein Precursors / Q000097:blood*; D014158:Transcription, Genetic; D059467:Transcriptome; D059289:Vascular Stiffness / Q000235:genetics*
chemical_list: D011498:Protein Precursors; C088633:proadrenomedullin; D053607:Adrenomedullin
keywords: adrenomedullin; gene expression; genome wide association scan; vascular stiffness