Synergistic Effects of ACE Insertion/Deletion and GNB3 C825T Polymorphisms on the Efficacy of PDE-5 Inhibitor in Patients with Pulmonary Hypertension

Respiration. 2016;91(2):132-40. doi: 10.1159/000443772. Epub 2016 Jan 28.

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.

Objectives: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Heterotrimeric GTP-Binding Proteins / genetics*
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / genetics
  • INDEL Mutation
  • Male
  • Middle Aged
  • Peptidyl-Dipeptidase A / genetics*
  • Phosphodiesterase 5 Inhibitors / therapeutic use*
  • Polymorphism, Genetic
  • Retrospective Studies
  • Sildenafil Citrate / therapeutic use
  • Tadalafil / therapeutic use
  • Treatment Outcome

Substances

  • GNB3 protein, human
  • Phosphodiesterase 5 Inhibitors
  • Tadalafil
  • Sildenafil Citrate
  • Peptidyl-Dipeptidase A
  • Heterotrimeric GTP-Binding Proteins