title: Functional prostacyclin synthase promoter polymorphisms. Impact in pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure, vascular remodeling, and ultimately right ventricular heart failure. PAH can have a genetic component (heritable PAH), most often through mutations of bone morphogenetic protein receptor 2, and idiopathic and associated forms. Heritable PAH is not completely penetrant within families, with approximately 20% concurrence of inactivating bone morphogenetic protein receptor 2 mutations and delayed onset of PAH disease. Because one of the treatment options is using prostacyclin analogs, we hypothesized that prostacyclin synthase promoter sequence variants associated with increased mRNA expression may play a protective role in the bone morphogenetic protein receptor 2 unaffected carriers.
  
  
  OBJECTIVE
  To characterize the range of prostacyclin synthase promoter variants and assess their transcriptional activities in PAH-relevant cell types. To determine the distribution of prostacyclin synthase promoter variants in PAH, unaffected carriers in heritable PAH families, and control populations.
  
  
  METHODS
  Polymerase chain reaction approaches were used to genotype prostacyclin synthase promoter variants in more than 300 individuals. Prostacyclin synthase promoter haplotypes' transcriptional activities were determined with luciferase reporter assays.
  
  
  RESULTS
  We identified a comprehensive set of prostacyclin synthase promoter variants and tested their transcriptional activities in PAH-relevant cell types. We demonstrated differences of prostacyclin synthase promoter activities dependent on their haplotype.
  
  
  CONCLUSIONS
  Prostacyclin synthase promoter sequence variants exhibit a range of transcriptional activities. We discovered a significant bias for more active prostacyclin synthase promoter variants in unaffected carriers as compared with affected patients with PAH.
authors.affiliation: 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Stearman
authors.forename: Amber R
authors.initials: AR
authors.lastname: Cornelius
authors.forename: Xiao
authors.initials: X
authors.lastname: Lu
authors.forename: David S
authors.initials: DS
authors.lastname: Conklin
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Del Rosario
authors.forename: Anita M
authors.initials: AM
authors.lastname: Lowe
authors.forename: Mihret T
authors.initials: MT
authors.lastname: Elos
authors.forename: Lynsey M
authors.initials: LM
authors.lastname: Fettig
authors.forename: Randall E
authors.initials: RE
authors.lastname: Wong
authors.forename: Naoko
authors.initials: N
authors.lastname: Hara
authors.forename: Joy D
authors.initials: JD
authors.lastname: Cogan
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Taylor
authors.forename: Brian B
authors.initials: BB
authors.lastname: Graham
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.forename: Mark W
authors.initials: MW
authors.lastname: Geraci
mesh_terms: D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology; D018450:Disease Progression; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000502:physiology; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: D003577:Cytochrome P-450 Enzyme System; D052006:Bone Morphogenetic Protein Receptors, Type II; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase