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 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].

Conclusion: The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives.

Figures

Figure 1

Haploview-generated linkage disequilibrium map of ADRBK1 SNPs in blacks and whites. The minimum minor allele frequency in each population was 5%. The numbers within boxes indicate the r2 values between the two corresponding SNPs. Haplotype blocks were defined by Haploview software with the default option of using the haplotype block definition used by Gabriel et al.[22] In blacks, three SNPs (rs7128315, -703 T/C and rs948988) have a correlation coefficient r2>0.8.

Figure 2

Blood pressure (BP) response to atenolol (ATEN) and hydrochlorothiazide(HCTZ) by race and GRK5 Gln41Gln vs. GRK5 Leu-Carrier. Data are presented as mean change from baseline with standard error. Dark barsGRK5 Gln41Gln; light barsGRK5 Leu-Carrier; SBP systolic blood pressure; DBP diastolic blood pressure

Figure 3

Adjusted odds ratio for GRK5 Gln41Leu on probability of experiencing the INVEST primary outcome (first occurrence of death, nonfatal myocardial infarction, or stroke). Odds ratios smaller than 1 indicate lower likelihood of Leu allele carriers experiencing the INVEST primary outcome. Odds ratios greater than 1 indicate greater likelihood of Leu allele carriers experiencing the INVEST primary outcome. ALL entire cohort, BB β-blocker strategy, CCB calcium channel blocker strategy. Asterisk denotes P = 0.0222, Statistical comparisons are between patients who were Gln41Gln homozygote and patients who were Leu allele carriers. Analyses were adjusted for age, sex, race/ethnicity, previous myocardial infarction, prior heart failure; body mass index, previous stroke or transient ischemic attack, history of peripheral vascular disease, smoking, diabetes, renal insufficiency, and coronary artery bypass graft surgery