Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients.
OBJECTIVE
The G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 are important regulators of β-adrenergic signaling. This study characterized single-nucleotide polymorphisms (SNPs) in the GRK2 gene (ADRBK1) and determined if these and a GRK5 Gln41Leu polymorphism affect the blood pressure (BP) response to atenolol or hydrochlorothiazide or adverse cardiovascular outcomes in hypertensives.


METHODS
ADRBK1 regions were sequenced for 48 individuals. Putative functional SNPs were tested for mRNA expression differences in 96 lymphoblastoid cell line samples and 12 leukocyte samples from hypertensives. BP response to atenolol and hydrochlorothiazide by ADRBK1 SNPs and GRK5 Gln41Leu was tested in 418 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses Study using linear regression. The influence of ADRBK1 SNPs and GRK5 Gln41Leu on death, myocardial infarction or stroke in treated hypertensives was evaluated in a case-control cohort (1 : 3) of the International Verapamil SR/Trandolapril Study GENEtic Substudy using logistic regression models.


RESULTS
A novel ADRBK1 promoter SNP was not associated with differential GRK2 expression. GRK5 Leu41 decreased the risk for adverse cardiovascular outcomes independent of treatment strategy (adjusted odds ratio 0.535, 95% confidence interval: 0.313-0.951, P=0.0222), but was not associated with BP response to antihypertensive medication. An ADRBK1 SNP (rs1894111 G>A) showed a signal for association with systolic and diastolic BP response to hydrochlorothiazide in Whites [diastolic BP: -11.29±3.74 (G/A) versus -4.26±4.79 mmHg (G/G), P=0.0034 and systolic BP: -18.37±14.90 (G/A), -8.11±7.55 mmHg (G/G), P=0.0191].


CONCLUSIONS
The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives.
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.
Maximilian T
MT
Lobmeyer
Liewei
L
Wang
Issam
I
Zineh
Stephen T
ST
Turner
John G
JG
Gums
Arlene B
AB
Chapman
Rhonda M
RM
Cooper-DeHoff
Amber L
AL
Beitelshees
Kent R
KR
Bailey
Eric
E
Boerwinkle
Carl J
CJ
Pepine
Julie A
JA
Johnson
D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics / Q000517:prevention & control; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics*; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D055815:Young Adult
D000959:Antihypertensive Agents; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human