Dataset Information

Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients.

ABSTRACT: OBJECTIVES:The G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 are important regulators of ?-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]. CONCLUSION:The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives.

SUBMITTER: Lobmeyer MT

PROVIDER: S-EPMC3028503 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients.

Lobmeyer Maximilian T MT Wang Liewei L Zineh Issam I Turner Stephen T ST Gums John G JG Chapman Arlene B AB Cooper-DeHoff Rhonda M RM Beitelshees Amber L AL Bailey Kent R KR Boerwinkle Eric E Pepine Carl J CJ Johnson Julie A JA

Pharmacogenetics and genomics 20110101 1

<h4>Objectives</h4>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.<h4>Methods</h4>ADRBK1 regions were sequenced for 48 individuals. Putative functional SNPs were ...[more]

PMID: 21127457

Similar Datasets

Project description:Liver X receptor-? (LXRA) is a nuclear receptor that regulates genes important in cholesterol homeostasis and inflammation. Several single nucleotide polymorphisms (SNPs) in the LXRA gene (NR1H3) have been earlier associated with metabolic phenotypes (dyslipidemia and elevated body mass index). Metabolic dysregulation is a major contributor to coronary disease; therefore, we assessed LXRA in International Verapamil Sustained Release SR Trandolapril Study Genetic Substudy (INVEST-GENES), a genetic-substudy of a large clinical trial in patients with hypertension and coronary artery disease.Seven tag SNPs in the LXRA gene region (NR1H3) were selected for study: rs11039149, rs12221497, rs2279238, rs7120118, rs326213, rs11039159, and rs10501321. One thousand fifty-nine patients were genotyped from the INVEST-GENES case-control set (verapamil-sustained release-based or atenolol-based treatment strategies) that comprised of 297 cases frequency matched (approximately 2.5:1) with that of event-free controls by sex and race. The primary outcome was defined as first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Adjusted odds ratios (ORs) were calculated using logistic regression.Three of the seven SNPs were associated with significant effects on the primary outcome in nonBlacks. The variant G allele of rs11039149 and the variant A allele of rs12221497 were associated with reduced risk of experiencing the primary outcome [OR: 0.62, confidence interval (CI): 0.45-0.85, P=0.003 and OR: 0.60, CI: 0.39-0.91, P=0.016, respectively]. The rs2279238 genotype was associated with a significant increase in risk for the primary outcome (OR: 1.42, CI: 1.03-1.95, P=0.03). Furthermore, there was a significant genotype-treatment strategy interaction for carriers of the variant T allele of rs2279238 (OR for verapamil-sustained release strategy compared with atenolol strategy: 2.86, CI: 1.50-5.46, P=0.0015). Diplotype analyses showed that the SNPs are rarely coinherited and support the directionally opposite effects of the SNPs on the primary outcome.LXRA genotypes were associated with variable risk for cardiovascular outcomes and pharmacogenetic effect in INVEST-GENES. These novel findings suggest that LXRA is a genetic/pharmacogenetic target that should be further explored.

Dataset Information

Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients.

Publications

Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure