title: Synergistic Effects of ACE Insertion/Deletion and GNB3 C825T Polymorphisms on the Efficacy of PDE-5 Inhibitor in Patients with Pulmonary Hypertension.
abstract: BACKGROUND
  The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the C825T polymorphism in the G-protein β3 subunit gene (GNB3) are associated with the efficacy of phosphodiesterase-5 inhibitor (PDE-5I) in erectile dysfunction. In addition, GNB3 genotypes could be associated with clinical worsening in pulmonary hypertension (PH) treated with PDE-5I. However, no studies have described the synergistic effects of gene polymorphisms on drug efficacy in patients with PH.
  
  
  OBJECTIVE
  We aimed to examine the effects of combined ACE/GNB3 polymorphisms on the efficacy of PDE-5I in patients with PH.
  
  
  METHODS
  This was a retrospective uncontrolled study. Ninety patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH) were treated with PDE-5I. Freedom from clinical worsening and pre- and post-treatment parameters, including the 6-min walk distance (6MWD) and serum brain natriuretic peptide (BNP) levels, were compared between patients with ACE/GNB3 II/TT and non-II/TT genotypes.
  
  
  RESULTS
  Time to clinical worsening was significantly longer in patients with the II/TT genotype than in those with the non-II/TT genotype (5-year freedom from clinical worsening: 100 vs. 48.8%, respectively; p = 0.018), even in patients with CTEPH alone. Post-treatment 6MWD and BNP levels in patients with the II/TT genotype tended to be better than those in patients with the non-II/TT genotype. The ACE/GNB3 genotype was a significant predictor of clinical worsening, even after adjusting for pulmonary vascular resistance and 6MWD.
  
  
  CONCLUSIONS
  ACE and GNB3 polymorphisms may synergistically influence the efficacy of PDE-5I in patients with PH.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Nishimura
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanabe
authors.forename: Ayumi
authors.initials: A
authors.lastname: Sekine
authors.forename: Hajime
authors.initials: H
authors.lastname: Kasai
authors.forename: Rika
authors.initials: R
authors.lastname: Suda
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Kato
authors.forename: Takayuki
authors.initials: T
authors.lastname: Jujo
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Ayako
authors.initials: A
authors.lastname: Shigeta
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Sakao
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000235:genetics; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D000068677:Sildenafil Citrate / Q000627:therapeutic use; D000068581:Tadalafil / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C000595803:GNB3 protein, human; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D007703:Peptidyl-Dipeptidase A; D020962:Heterotrimeric GTP-Binding Proteins