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Clinical Chemistry 52: 352-360, 2006. First published January 26, 2006; 10.1373/clinchem.2005.059139
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(Clinical Chemistry. 2006;52:352-360.)
© 2006 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Single-Nucleotide Polymorphisms for Diagnosis of Salt-Sensitive Hypertension

Hironobu Sanada1, Junichi Yatabe1, Sanae Midorikawa1, Shigeatsu Hashimoto1, Tsuyoshi Watanabe1, Jason H. Moore2, Marylyn D. Ritchie2, Scott M. Williams3, John C. Pezzullo4, Midori Sasaki5, Gilbert M. Eisner4, Pedro A. Jose4 and Robin A. Felder5,a

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, and3 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.

aAddress correspondence to this author at: University of Virginia Center for the Health Sciences, PO Box 800403, Charlottesville, VA 22908. Fax 434-924-5718; 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 multifactor 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 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.




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