Christopher M. O'Connor, Mona Fiuzat, Peter E. Carson, Inder S. Anand, Jonathan F. Plehn, Stephen S. Gottlieb, Marc A. Silver, JoAnn Lindenfeld, Alan B. Miller, Michel White, Ryan Walsh, Penny Nelson, Allen Medway, Gordon Davis, Alastair D. Robertson, J. David Port, James Carr, Guinevere A. Murphy, Laura C. Lazzeroni, William T. Abraham, Stephen B. Liggett, Michael R. Bristow

Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology.