A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure.
Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.
Liggett
Stephen B
SB
Department of Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267, USA.
Cresci
Sharon
S
Kelly
Reagan J
RJ
Syed
Faisal M
FM
Matkovich
Scot J
SJ
Hahn
Harvey S
HS
Diwan
Abhinav
A
Martini
Jeffrey S
JS
Sparks
Li
L
Parekh
Rohan R
RR
Spertus
John A
JA
Koch
Walter J
WJ
Kardia
Sharon L R
SL
Dorn
Gerald W
GW
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D001741:Black or African American / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human