Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension

Hironobu Sanada, Junichi Yatabe, Sanae Midorikawa, Shigeatsu Hashimoto, Tsuyoshi Watanabe, Jason H. Moore, Marylyn Deriggi Ritchie, Scott M. Williams, John C. Pezzullo, Midori Sasaki, Gilbert M. Eisner, Pedro A. Jose, Robin A. Felder

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Abstract

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 (D 1R)-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 D 1R 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.

Original languageEnglish (US)
Pages (from-to)352-360
Number of pages9
JournalClinical Chemistry
Volume52
Issue number3
DOIs
StatePublished - Mar 1 2006

Fingerprint

Polymorphism
Renin
Single Nucleotide Polymorphism
Nucleotides
Salts
Hypertension
Genes
Sodium
G-Protein-Coupled Receptor Kinase 4
Genetic Models
Cytochrome P-450 CYP11B2
Natriuretic Agents
Multifactor Dimensionality Reduction
Blood pressure
Prodrugs
Genotype
Dopamine
Screening
Plasmas
Testing

All Science Journal Classification (ASJC) codes

  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Sanada, H., Yatabe, J., Midorikawa, S., Hashimoto, S., Watanabe, T., Moore, J. H., ... Felder, R. A. (2006). Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. Clinical Chemistry, 52(3), 352-360. https://doi.org/10.1373/clinchem.2005.059139
Sanada, Hironobu ; Yatabe, Junichi ; Midorikawa, Sanae ; Hashimoto, Shigeatsu ; Watanabe, Tsuyoshi ; Moore, Jason H. ; Ritchie, Marylyn Deriggi ; Williams, Scott M. ; Pezzullo, John C. ; Sasaki, Midori ; Eisner, Gilbert M. ; Jose, Pedro A. ; Felder, Robin A. / Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. In: Clinical Chemistry. 2006 ; Vol. 52, No. 3. pp. 352-360.
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abstract = "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 (D 1R)-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 D 1R 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.",
author = "Hironobu Sanada and Junichi Yatabe and Sanae Midorikawa and Shigeatsu Hashimoto and Tsuyoshi Watanabe and Moore, {Jason H.} and Ritchie, {Marylyn Deriggi} and Williams, {Scott M.} and Pezzullo, {John C.} and Midori Sasaki and Eisner, {Gilbert M.} and Jose, {Pedro A.} and Felder, {Robin A.}",
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Sanada, H, Yatabe, J, Midorikawa, S, Hashimoto, S, Watanabe, T, Moore, JH, Ritchie, MD, Williams, SM, Pezzullo, JC, Sasaki, M, Eisner, GM, Jose, PA & Felder, RA 2006, 'Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension', Clinical Chemistry, vol. 52, no. 3, pp. 352-360. https://doi.org/10.1373/clinchem.2005.059139

Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. / Sanada, Hironobu; Yatabe, Junichi; Midorikawa, Sanae; Hashimoto, Shigeatsu; Watanabe, Tsuyoshi; Moore, Jason H.; Ritchie, Marylyn Deriggi; Williams, Scott M.; Pezzullo, John C.; Sasaki, Midori; Eisner, Gilbert M.; Jose, Pedro A.; Felder, Robin A.

In: Clinical Chemistry, Vol. 52, No. 3, 01.03.2006, p. 352-360.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension

AU - Sanada, Hironobu

AU - Yatabe, Junichi

AU - Midorikawa, Sanae

AU - Hashimoto, Shigeatsu

AU - Watanabe, Tsuyoshi

AU - Moore, Jason H.

AU - Ritchie, Marylyn Deriggi

AU - Williams, Scott M.

AU - Pezzullo, John C.

AU - Sasaki, Midori

AU - Eisner, Gilbert M.

AU - Jose, Pedro A.

AU - Felder, Robin A.

PY - 2006/3/1

Y1 - 2006/3/1

N2 - 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 (D 1R)-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 D 1R 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.

AB - 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 (D 1R)-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 D 1R 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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Sanada H, Yatabe J, Midorikawa S, Hashimoto S, Watanabe T, Moore JH et al. Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. Clinical Chemistry. 2006 Mar 1;52(3):352-360. https://doi.org/10.1373/clinchem.2005.059139