title: G protein receptor kinase 4 polymorphisms: β-blocker pharmacogenetics and treatment-related outcomes in hypertension.
abstract: G protein-coupled receptor kinases (GRKs) are important regulatory proteins for many G protein-coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized that 3 nonsynonymous GRK4 single-nucleotide polymorphisms, R65L (rs2960306), A142V (rs1024323), and A486V (rs1801058), would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long-term cardiovascular outcomes (all-cause death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR-based antihypertensive strategy. GRK4 single-nucleotide polymorphisms were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In whites and blacks, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (-9.1±6.8 versus -6.8±7.1 versus -5.3±6.4 mm Hg in participants with 0, 1, and 2 copies of 65L-142V, respectively; P=0.0088). One thousand four hundred sixty participants with hypertension and coronary artery disease from the INternational VErapamil SR/Trandolapril STudy (INVEST) were genotyped, and variant alleles of all 3 GRK4 single-nucleotide polymorphisms were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (odds ratio, 2.29 [1.48-3.55]; P=0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest that the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R homozygotes, suggesting a potential interaction between these 2 genes.
authors.affiliation: Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida College of Pharmacy, 1600 SW Archer Rd, Room PG-22, Box 100486, Gainesville, FL 32610-0486, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Vandell
authors.forename: Maximilian T
authors.initials: MT
authors.lastname: Lobmeyer
authors.forename: Brian E
authors.initials: BE
authors.lastname: Gawronski
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: John G
authors.initials: JG
authors.lastname: Gums
authors.forename: Amber L
authors.initials: AL
authors.lastname: Beitelshees
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.forename: Kent R
authors.initials: KR
authors.lastname: Bailey
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001262:Atenolol / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics; D005260:Female; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D006852:Hydrochlorothiazide; D001262:Atenolol; D014700:Verapamil; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human