title: A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, Ohio 45267, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.forename: Sharon
authors.initials: S
authors.lastname: Cresci
authors.forename: Reagan J
authors.initials: RJ
authors.lastname: Kelly
authors.forename: Faisal M
authors.initials: FM
authors.lastname: Syed
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.forename: Harvey S
authors.initials: HS
authors.lastname: Hahn
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Martini
authors.forename: Li
authors.initials: L
authors.lastname: Sparks
authors.forename: Rohan R
authors.initials: RR
authors.lastname: Parekh
authors.forename: John A
authors.initials: JA
authors.lastname: Spertus
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: 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
chemical_list: D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human