Combinatorial pharmacogenetic interactions of bucindolol and β1, α2C adrenergic receptor polymorphisms.
BACKGROUND
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.


METHODS
In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β(1)389 and α(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β(1)389 AR variants was measured in human explanted left ventricles.


RESULTS
The combination of β(1)389 Arg+α(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β(1)389 Arg homozygotes+α(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β(1)389 Arg vs. Gly ARs, which converts α(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit.


CONCLUSIONS
On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β(1)389 Arg homozygotes), intermediate (β(1)389 Gly carriers+α(2C)322-325 Wt homozygotes), and no (β(1)389 Gly carriers+α(2C)322-325 Del carriers) efficacy.
Division of Cardiology, Duke University Medical Center/Duke Clinical Research Institute, Durham, North Carolina, United States of America. christophe.oconnor@duke.edu
Christopher M
CM
O'Connor
Mona
M
Fiuzat
Peter E
PE
Carson
Inder S
IS
Anand
Jonathan F
JF
Plehn
Stephen S
SS
Gottlieb
Marc A
MA
Silver
JoAnn
J
Lindenfeld
Alan B
AB
Miller
Michel
M
White
Ryan
R
Walsh
Penny
P
Nelson
Allen
A
Medway
Gordon
G
Davis
Alastair D
AD
Robertson
J David
JD
Port
James
J
Carr
Guinevere A
GA
Murphy
Laura C
LC
Lazzeroni
William T
WT
Abraham
Stephen B
SB
Liggett
Michael R
MR
Bristow
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000235:genetics*
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; C024307:bucindolol; D009638:Norepinephrine