title: Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases.
  
  
  OBJECTIVE
  To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs).
  
  
  METHODS
  A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort.
  
  
  RESULTS
  Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months.
  
  
  CONCLUSIONS
  ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.
authors.affiliation: 1 Division of Cardiovascular Disease, Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Benza
authors.affiliation: 2 Division of Cardiovascular Disease, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Mardi
authors.initials: M
authors.lastname: Gomberg-Maitland
authors.affiliation: 3 Division of Cardiovascular Disease, Department of Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Teresa
authors.initials: T
authors.lastname: Demarco
authors.affiliation: 4 Baylor College of Medicine, Houston, Texas.
authors.forename: Adaani E
authors.initials: AE
authors.lastname: Frost
authors.affiliation: 5 Department of Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Medical Education, ECZ, Otwock, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Torbicki
authors.affiliation: 6 Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langleben
authors.affiliation: 7 Cardiopulmonary Department, National Heart Institute, Mexico City, Mexico.
authors.forename: Tomas
authors.initials: T
authors.lastname: Pulido
authors.affiliation: 1 Division of Cardiovascular Disease, Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Correa-Jaque
authors.affiliation: 1 Division of Cardiovascular Disease, Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Passineau
authors.affiliation: 8 Department of Epidemiology and.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Wiener
authors.affiliation: 9 Institute of Physical and Chemical Research (RIKEN), Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamari
authors.affiliation: 9 Institute of Physical and Chemical Research (RIKEN), Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hirota
authors.affiliation: 9 Institute of Physical and Chemical Research (RIKEN), Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: 10 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000235:genetics*; D005080:Exercise Test; D017079:Exercise Tolerance; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1
keywords: endothelin receptor antagonists; pharmacogenetics; polymorphisms; pulmonary arterial hypertension