G Protein Receptor Kinase 4 Polymorphisms beta-Blocker Pharmacogenetics and Treatment-Related Outcomes in Hypertension

• Type of Material: Article
• Authors: Alexander G. Vandell, University of Florida; Maximilian T. Lobmeyer, University of Florida; Brian E. Gawronski, University of Florida; Taimour Y. Langaee, University of Florida; Yan Gong, University of Florida; John G. Gums, University of Florida; Amber L. Beitelshees, University of Maryland; Stephen T. Turner, Mayo Clinic; Arlene B Chapman, Emory University; Rhonda M. Cooper-DeHoff, University of Florida; Kent R. Bailey, Mayo Clinic; Eric Boerwinkle, University of Texas Health Science Center; Carl J. Pepine, University of Florida; Stephen B. Liggett, University of South Florida; Julie A. Johnson, University of Florida
• Language: English
• Date: 2012-10-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.198721
• Title of Journal or Parent Work: Hypertension
• ISSN: 0194-911X
• Volume: 60
• Issue: 4
• Start Page: 957
• End Page: 964
• Grant/Funding Information: This work is supported by a grant from the National Institutes of Health (Bethesda, MD), grant U01 GM074492, funded as part of the Pharmacogenetics Research Network.; Additional support for this work includes: National Institutes of Health grants R01 HL74730, K23 grants HL091120 (A.L. Beitelshees) and HL086558 (R.M. Cooper-DeHoff); NIH CTSA grants UL1- RR092890 (University of Florida), UL1-RR025008 (Emory University), and UL1-RR024150 (Mayo Clinic); and grants from Abbott Laboratories, the University of Florida Opportunity Fund, and the Mayo Foundation.
• Keywords: atenolol; GENE VARIANTS; G protein-coupled receptor kinase; beta-blocker; ADRB1; outcomes; pharmacogenetics; Life Sciences & Biomedicine; Cardiovascular System & Cardiology; SINGLE-NUCLEOTIDE POLYMORPHISMS; ASSOCIATION; DESENSITIZATION; hypertension; MECHANISMS; COUPLED RECEPTOR; DISEASE; HEART-FAILURE; Science & Technology; Peripheral Vascular Disease; BLOOD-PRESSURE RESPONSE; GRK4
• Research Categories: Biology, Genetics; Health Sciences, Pharmacology

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.