Single-Nucleotide Polymorphisms for Diagnosis of Salt-Sensitive Hypertension

• Published in: Clinical chemistry (Baltimore, Md.) Md.), 2006-03, Vol.52 (3), p.352-360
• Main Authors: Sanada, Hironobu, Yatabe, Junichi, Midorikawa, Sanae, Hashimoto, Shigeatsu, Watanabe, Tsuyoshi, Moore, Jason H, Ritchie, Marylyn D, Williams, Scott M, Pezzullo, John C, Sasaki, Midori, Eisner, Gilbert M, Jose, Pedro A, Felder, Robin A
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Asian Continental Ancestry Group; Biological and medical sciences; Biological Transport; Blood Pressure; Cohort Studies; Diet; Dopamine - analogs & derivatives; Dopamine - pharmacology; Female; Fundamental and applied biological sciences. Psychology; G-Protein-Coupled Receptor Kinase 4; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Hypertension - diagnosis; Hypertension - physiopathology; Investigative techniques, diagnostic techniques (general aspects); Japan; Male; Medical sciences; Middle Aged; Models, Genetic; Natriuretic Agents - pharmacology; Polymorphism, Genetic; Prodrugs - pharmacology; Protein-Serine-Threonine Kinases - genetics; Receptors, Dopamine D1 - agonists; Receptors, Dopamine D1 - physiology; Renin - blood; Salts; Sodium; Sodium - metabolism; Sodium Chloride, Dietary - administration & dosage
• ISSN: 0009-9147; 1530-8561
• DOI: 10.1373/clinchem.2005.059139

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. 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 multifactor dimensionality reduction method to determine the genotype associated with salt sensitivity (> or =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). 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 > or =3 GRK4 gene variants. GRK4 gene variants are associated with SS and low-renin hypertension. However, the genetic model predicting SS hypertension 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.