Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension.
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 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).


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 > or =3 GRK4 gene variants.


CONCLUSIONS
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.
Sanada
Hironobu
H
Third Department of Internal Medicine, Fukushima Medical University, School of Medicine, Fukushima City, Japan.
Yatabe
Junichi
J
Midorikawa
Sanae
S
Hashimoto
Shigeatsu
S
Watanabe
Tsuyoshi
T
Moore
Jason H
JH
Ritchie
Marylyn D
MD
Williams
Scott M
SM
Pezzullo
John C
JC
Sasaki
Midori
M
Eisner
Gilbert M
GM
Jose
Pedro A
PA
Felder
Robin A
RA
D044466:Asian People; D001692:Biological Transport; D001794:Blood Pressure; D015331:Cohort Studies; D004032:Diet; D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D054771:G-Protein-Coupled Receptor Kinase 4; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000175:diagnosis* / Q000503:physiopathology; D007564:Japan; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D045283:Natriuretic Agents / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011355:Prodrugs / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000502:physiology; D012083:Renin / Q000097:blood; D012964:Sodium / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*
D045283:Natriuretic Agents; D011355:Prodrugs; D017447:Receptors, Dopamine D1; D017673:Sodium Chloride, Dietary; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; D012083:Renin; C052143:docarpamine; D004298:Dopamine