Abstract 5413: G Protein-Coupled Receptor Type 4 Gene Variants and Response to Antihypertensive Medication

Abstract

Renal dopamine counteracts the prohypertensive and sodium retaining actions of the renin-angiotensin system (RAS). In genetic hypertension, the ability of dopamine to counteract the actions of the RAS is impaired by an increased constitutive activity of genetic variants of G protein-coupled receptor kinase type 4 (GRK4) that desensitize DRD1 dopamine receptors. Selective renal silencing of Grk4 improves DRD1 function and ameliorates the hypertension in spontaneously hypertensive rats. GRK4 γ wild-type transgenic mice are normotensive and salt-resistant; GRK4 γ 142V transgenic mice are hypertensive while Grk4 γ 486V transgenic mice are salt-sensitive. Renal Grk4 and angiotensin type 1 receptor (AT1R) interact to regulate blood pressure (BP) in rats and GRK4 γ 142V transgenic mice. We tested the association between essential hypertension in 1102 Japanese (616 cases and 486 controls) and single nucleotide polymorphisms (SNPs)/markers in the genes encoding GRK4, ACE, angiotensinogen, AT1R, aldosterone synthase, plasminogen activator inhibitor-1, DRD1, and GNB3. In addition, GRK4 genotype and the response to angiotensin receptor blockers (ARBs) without or with diuretic therapy in 161 Japanese with mild essential hypertension (systolic[SBP]/diastolic [DBP]=148.5±3.3/92.9±2.9 mmHg, age 55±10 yrs) were examined. All three GRK4 SNPs (R65L, A142V, and A486V) associated with hypertension (allelic and genotypic tests, P<4×10 −8 for all three markers). The GRK4 three variant haplotype odds ratio for hypertension was 2.49(P<4×10 −14 ). In the responders to ARBs (n=67) BP decreased to 132.8±3.7/84.7±3.1 mmHg and was highly associated with the GRK4142V (P<0.003). The absolute decrease in SBP and DBP in response to ARB was also associated with GRK4142V (P<0.007). The addition of a diuretic (bumetanide) to the non-responders (n=94) decreased BP (127.8±5.0/84.4±2.7, n=47) which was associated with GRK4A486V (P<0.005). The GRK4 variant 142V may be both strongly predisposing to essential hypertension and predictive of the initial response to ARB monotherapy while the GRK4 variant 486V may be predictive of the response to dual therapy with an ARB and a diuretic. Therefore, pharmacogenetics of GRK4 is important in guiding the therapy for hypertension.