title: Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension.
abstract: Idiopathic pulmonary arterial hypertension (IPAH) is usually without an identified genetic cause, despite clinical and molecular similarity to bone morphogenetic protein receptor type 2 mutation-associated heritable pulmonary arterial hypertension (PAH). There is phenotypic heterogeneity in IPAH, with a minority of patients showing long-term improvement with calcium channel-blocker therapy.
  
  
  
  We sought to identify gene variants (GVs) underlying IPAH and determine whether GVs differ in vasodilator-responsive IPAH (VR-PAH) versus vasodilator-nonresponsive IPAH (VN-PAH).
  
  
  
  We performed whole-exome sequencing (WES) on 36 patients with IPAH: 17 with VR-PAH and 19 with VN-PAH. Wnt pathway differences were explored in human lung fibroblasts.
  
  
  
  We identified 1,369 genes with 1,580 variants unique to IPAH. We used a gene ontology approach to analyze variants and identified overrepresentation of several pathways, including cytoskeletal function and ion binding. By mapping WES data to prior genome-wide association study data, Wnt pathway genes were highlighted. Using the connectivity map to define genetic differences between VR-PAH and VN-PAH, we found enrichment in vascular smooth muscle cell contraction pathways and greater genetic variation in VR-PAH versus VN-PAH. Using human lung fibroblasts, we found increased stimulated Wnt activity in IPAH versus controls.
  
  
  
  A pathway-based analysis of WES data in IPAH demonstrated multiple rare GVs that converge on key biological pathways, such as cytoskeletal function and Wnt signaling pathway. Vascular smooth muscle contraction-related genes were enriched in VR-PAH, suggesting a potentially different genetic predisposition for VR-PAH. This pathway-based approach may be applied to next-generation sequencing data in other diseases to uncover the contribution of unexpected or multiple GVs to a phenotype.
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.affiliation: 2 Department of Biomedical Informatics.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine.
authors.forename: James
authors.initials: J
authors.lastname: West
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine.
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.affiliation: 3 Division of Cardiology, University of Chicago, Chicago, Illinois; and.
authors.forename: Stuart
authors.initials: S
authors.lastname: Rich
authors.affiliation: 4 Department of Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine.
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Robbins
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: 5 Department of Pediatric Medical Genetics, and.
authors.forename: Joy
authors.initials: J
authors.lastname: Cogan
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine.
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.affiliation: 2 Department of Biomedical Informatics.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: 2 Department of Biomedical Informatics.
authors.forename: Christa
authors.initials: C
authors.lastname: Gaskill
authors.affiliation: 2 Department of Biomedical Informatics.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jetter
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kropski
authors.affiliation: 2 Department of Biomedical Informatics.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Majka
authors.affiliation: 6 Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
mesh_terms: D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014661:Vasoconstriction / Q000235:genetics*
keywords: pulmonary arterial hypertension; vasodilator responsive; whole-exome sequencing