Received on August 31, 2005
Accepted on December 29, 2005

Molecular Diagnostics and Genetics

Single-Nucleotide Polymorphisms for Diagnosis of Salt-Sensitive Hypertension

¹ Third Department of Internal Medicine, Fukushima Medical University, School of Medicine, Fukushima City, Japan
² Department of Molecular Physiology and Biophysics and Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN
³ Division of Cardiovascular Medicine, Center for Human Genetics Research, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
⁴ Department of Pediatrics, Georgetown University Medical Center, Washington, DC
⁵ Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA 22908

^* To whom correspondence should be addressed. E-mail: rfelder{at}virginia.edu.

Background: Salt-sensitive (SS) hypertension affects >30 million Americans and is often associated with low plasma renin activity. We tested the diagnostic validity of several candidate genes for SS and low-renin hypertension.

Methods: In Japanese patients with newly diagnosed, untreated hypertension (n = 184), we studied polymorphisms in 10 genes, including G protein-coupled receptor kinase type 4 (GRK4), some variations of which are associated with hypertension and impair D₁ receptor (D₁R)-inhibited renal sodium transport. We used the multifactorial dimensionality reduction method to determine the genotype associated with salt sensitivity (10% increase in blood pressure with high sodium intake) or low renin. To determine whether the GRK4 genotype is associated with impaired D₁R function, we tested the natriuretic effect of docarpamine, a dopamine prodrug, in normotensive individuals with or without GRK4 polymorphisms (n = 18).

Results: A genetic model based on GRK4 R65L, GRK4 A142V, and GRK4 A486V was 94.4% predictive of SS hypertension, whereas the single-locus model with only GRK4 A142V was 78.4% predictive, and a 2-locus model of GRK4 A142V and CYP11B2 C-344T was 77.8% predictive of low-renin hypertension. Sodium excretion was inversely related to the number of GRK4 variants in hypertensive persons, and the natriuretic response to dopaminergic stimulation was impaired in normotensive persons having 3 GRK4 gene variants.

Conclusions: GRK4 gene variants are associated with SS and low-renin hypertension. However, the genetic model predicting SS is different from the model for low renin, suggesting genetic differences in these 2 phenotypes. Like low-renin testing, screening for GRK4 variants may be a useful diagnostic adjunct for detection of SS hypertension.