title: G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: results of A-HeFT.
abstract: OBJECTIVE
  The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial).
  
  
  BACKGROUND
  GNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans.
  
  
  METHODS
  A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets.
  
  
  RESULTS
  The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H = 0.50 ± 1.6; placebo = -0.11 ± 1.8, p = 0.02), QoL (FDC I/H = 0.69 ± 1.4; placebo = 0.24 ± 1.5, p = 0.04), and event-free survival (hazard ratio: 0.51, p = 0.047), but not in subjects with the C allele (for CS, FDC I/H = -0.05 ± 1.7; placebo = -0.09 ± 1.7, p = 0.87; for QoL, FDC I/H = 0.28 ± 1.5; placebo = 0.14 ± 1.5, p = 0.56; and for event-free survival, p = 0.35).
  
  
  CONCLUSIONS
  The GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: mcnamaradm@upmc.edu.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: McNamara
authors.affiliation: Columbia University College of Physicians and Surgeons, New York, New York.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Taylor
authors.affiliation: Independent consultant, Dover, Massachusetts.
authors.forename: S William
authors.initials: SW
authors.lastname: Tam
authors.affiliation: Consultant, Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Worcel
authors.affiliation: Division of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Clyde W
authors.initials: CW
authors.lastname: Yancy
authors.affiliation: Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Karen
authors.initials: K
authors.lastname: Hanley-Yanez
authors.affiliation: University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jay N
authors.initials: JN
authors.lastname: Cohn
authors.affiliation: Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
mesh_terms: D001741:Black or African American / Q000235:genetics; D000704:Analysis of Variance; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D006830:Hydralazine / Q000627:therapeutic use*; D007548:Isosorbide Dinitrate / Q000627:therapeutic use*; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011788:Quality of Life; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000235:genetics
chemical_list: D004338:Drug Combinations; C000595803:GNB3 protein, human; D014665:Vasodilator Agents; C431665:isosorbide-hydralazine combination; D006830:Hydralazine; D020962:Heterotrimeric GTP-Binding Proteins; D007548:Isosorbide Dinitrate
keywords: heart failure; outcomes; pharmacogenetics; race