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Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients
Maximilian T Lobmeyer1, Liewei Wang, Issam Zineh
1Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.
Pharmacogenetics and Genomics
|December 4, 2010
Summary
The GRK5 Leu41 allele offers protection against adverse cardiovascular events in hypertensive patients. Certain GRK2 gene variations may influence blood pressure response to hydrochlorothiazide.
Area of Science:
- Pharmacogenomics
- Cardiovascular Medicine
- Genetics
Background:
- G-protein-coupled receptor kinases (GRKs) regulate beta-adrenergic signaling.
- GRK2 and GRK5 play critical roles in cardiovascular function and drug response.
Purpose of the Study:
- To investigate single-nucleotide polymorphisms (SNPs) in the GRK2 gene (ADRBK1).
- To assess the impact of GRK2 SNPs and a GRK5 Gln41Leu polymorphism on blood pressure response to atenolol or hydrochlorothiazide.
- To evaluate the effect of these genetic variations on adverse cardiovascular outcomes in hypertensive individuals.
Main Methods:
- Sequencing of ADRBK1 regions and identification of putative functional SNPs.
- mRNA expression analysis in lymphoblastoid cells and leukocytes.
- Association studies using data from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and International Verapamil SR/Trandolapril Study GENEtic Substudy (TIGS).
Main Results:
- A novel ADRBK1 promoter SNP did not affect GRK2 expression.
- The GRK5 Gln41Leu polymorphism (Leu41 allele) was associated with a reduced risk of adverse cardiovascular outcomes (OR 0.535, P=0.0222).
- An ADRBK1 SNP (rs1894111 G>A) showed a trend towards association with systolic and diastolic blood pressure response to hydrochlorothiazide in White patients.
Conclusions:
- The GRK5 Leu41 allele confers a protective effect against adverse cardiovascular outcomes in treated hypertensive patients.
- Specific GRK2 gene variants may influence individual responses to hydrochlorothiazide treatment.
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