title: Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension.
abstract: BACKGROUND
  Heterogeneity in response to treatment of pulmonary arterial hypertension (PAH) is a major challenge to improving outcome in this disease. Although vasodilator-responsive PAH (VR-PAH) accounts for a minority of cases, VR-PAH has a pronounced response to calcium channel blockers and better survival than vasodilator-nonresponsive PAH (VN-PAH). We hypothesized that VR-PAH has a different molecular cause from VN-PAH that can be detected in the peripheral blood.
  
  
  RESULTS
  Microarrays of cultured lymphocytes from VR-PAH and VN-PAH patients followed at Vanderbilt University were performed with quantitative polymerase chain reaction performed on peripheral blood for the 25 most different genes. We developed a decision tree to identify VR-PAH patients on the basis of the results with validation in a second VR-PAH cohort from the University of Chicago. We found broad differences in gene expression patterns on microarray analysis including cell-cell adhesion factors and cytoskeletal and rho-GTPase genes. Thirteen of 25 genes tested in whole blood were significantly different: EPDR1, DSG2, SCD5, P2RY5, MGAT5, RHOQ, UCHL1, ZNF652, RALGPS2, TPD52, MKNL1, RAPGEF2, and PIAS1. Seven decision trees were built with the use of expression levels of 2 genes as the primary genes: DSG2, a desmosomal cadherin involved in Wnt/β-catenin signaling, and RHOQ, which encodes a cytoskeletal protein involved in insulin-mediated signaling. These trees correctly identified 5 of 5 VR-PAH patients in the validation cohort.
  
  
  CONCLUSIONS
  VR-PAH and VN-PAH can be differentiated with the use of RNA expression patterns in peripheral blood. These differences may reflect different molecular causes of the 2 PAH phenotypes. This biomarker methodology may identify PAH patients who have a favorable treatment response.
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.). anna.r.hemnes@vanderbilt.edu.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Trammell
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Stuart
authors.initials: S
authors.lastname: Rich
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Hui
authors.initials: H
authors.lastname: Nian
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Niki
authors.initials: N
authors.lastname: Penner
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Mitchell
authors.initials: M
authors.lastname: Funke
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Lisa
authors.initials: L
authors.lastname: Wheeler
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Robbins
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.affiliation: From the Division of Allergy, Pulmonary, and Critical Care Medicine (A.R.H., A.W.T., N.P., M.F., L.W., I.M.R., J.H.N., J.W.) and Department of Biostatistics (C.Y., H.N.), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Queen's University, Kingston, Ontario, Canada (S.L.A.); Division of Cardiology, University of Chicago, Chicago, IL (S.R.); and Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (E.D.A.).
authors.forename: James
authors.initials: J
authors.lastname: West
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000235:genetics*; D008214:Lymphocytes / Q000473:pathology / Q000502:physiology*; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D014664:Vasodilation / Q000502:physiology*; D055815:Young Adult
keywords: biomarkers; pulmonary hypertension; treatment