The G Protein–Coupled Receptor Kinase 4 Gene Affects Blood Pressure in Young Normotensive Twins

Abstract

G protein-coupled receptor kinase 4 (GRK4) is involved in activity of dopamine receptors in renal proximal tubules and thus mediates sodium reabsorption and blood pressure (BP) regulation. The present study evaluated the impact of the GRK4 gene variants on BP levels in normotensive adolescents and young adults. Three functional polymorphisms of R65L, A142V, and A486V were genotyped in 934 white and African American (44.2%) twin subjects (17.4 +/- 3.4 years of age). A number of association approaches including single-locus analyses, haplotype trend regression analyses, and sib-pair transmission disequilibrium tests were carried out. Single-locus analyses revealed a significant interaction between R65L and age for SBP (P = .019) with an obvious gene-dose effect. In L65L homozygotes SBP showed the steepest increase with age (beta = 0.85, P = .003), R65L heterozygotes showed the next steepest increase (beta = 0.54, P < .001), and the effect of age on SBP was absent in R65R homozygotes. Stratified analyses showed that the SBP increasing effect of the 65L allele was significant only in the older group of subjects (114.1 +/- 11.1 mm Hg v 110.1 +/- 9.6 mm Hg, P = .024). Sib-pair transmission disequilibrium tests analyses in 72 informative dizygotic twin pairs confirmed the significant effect of the 65L on SBP; carriers of the 65L allele had a higher SBP compared with noncarriers (110.3 +/- 8.2 v 107.3 +/- 7.8 mm Hg, P = .047). Haplotype analyses uncovered an interaction between haplotype 65L-142V-486A and age for SBP (P = .017); individuals who were homozygous for haplotype 65L-142V-A486 showed a 1.05-mm Hg steeper increase in SBP per year increase in age compared with those homozygous for the most common R65-A142-A486 haplotype. Our data indicate that the R65L polymorphism of the GRK4 gene plays a role in BP regulation in adolescents and young adults.