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A functional variant of the NEDD4L gene is associated with beneficial treatment response with β-blockers and diuretics in hypertensive patients.

Svensson, Patrik LU ; Wahlstrand, Björn; Almgren, Peter LU ; Dahlberg, Jonas LU ; Fava, Cristiano LU ; Kjeldsen, Sverre; Hedner, Thomas and Melander, Olle LU (2011) In Journal of Hypertension 29(2). p.388-395
Abstract
OBJECTIVE: The capability of the protein NEDD4L to reduce renal tubular expression of epithelial Na+ channel (ENaC) is influenced by a functional rs4149601 G→A NEDD4L polymorphism. As diuretics and β-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the β-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease would be greater in patients with the highest ENaC expression (rs4149601 G-allele), whereas there would be no such genetically mediated differences in treatment efficacy among patients treated with the vasodilator diltiazem. METHODS: We related rs4149601 status to 6-month blood pressure reduction and risk of cardiovascular events in 5152 hypertensive... (More)
OBJECTIVE: The capability of the protein NEDD4L to reduce renal tubular expression of epithelial Na+ channel (ENaC) is influenced by a functional rs4149601 G→A NEDD4L polymorphism. As diuretics and β-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the β-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease would be greater in patients with the highest ENaC expression (rs4149601 G-allele), whereas there would be no such genetically mediated differences in treatment efficacy among patients treated with the vasodilator diltiazem. METHODS: We related rs4149601 status to 6-month blood pressure reduction and risk of cardiovascular events in 5152 hypertensive patients (DBP ≥ 100 mmHg) from the Nordic Diltiazem Study (NORDIL) randomized to either β-blocker and/or diuretic-based treatment or diltiazem-based treatment. RESULTS: In patients on β-blocker or diuretic monotherapy, carriers of the G-allele had greater SBP reduction (19.5 ± 16.8 vs. 15.0 ± 19.3 mmHg, P < 0.001) and DBP reduction (15.4 ± 8.3vs. 14.1 ± 8.4 mmHg, P = 0.02) and during 4.5 years of follow-up among patients randomized to β-blockers and/or diuretics, carriers of the G-allele had greater protection from cardiovascular events [relative risk (RR) = 0.52, 95% confidence interval (CI) = 0.36-0.74, P < 0.001] as compared to AA homozygotes. Within the diltiazem group, there was no difference in blood pressure reduction or risk of cardiovascular events according to genotype. CONCLUSION: The functional NEDD4L rs4149601 polymorphism influences the efficacy of β-blocker and/or diuretic-based antihypertensive treatment both in terms of blood pressure reduction and cardiovascular disease protection, whereas diltiazem-based antihypertensive treatment efficacy is not influenced by this NEDD4L polymorphism. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
hypertension treatment, ENaC, NORDIL, pharmacogenetics
in
Journal of Hypertension
volume
29
issue
2
pages
388 - 395
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000285744600030
  • pmid:21052022
  • scopus:78651273887
ISSN
1473-5598
DOI
10.1097/HJH.0b013e3283410390
language
English
LU publication?
yes
id
9ecf3360-b098-489c-bfbd-7a46fad6e564 (old id 1732300)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21052022?dopt=Abstract
date added to LUP
2010-12-01 10:31:49
date last changed
2017-05-28 04:02:38
@article{9ecf3360-b098-489c-bfbd-7a46fad6e564,
  abstract     = {OBJECTIVE: The capability of the protein NEDD4L to reduce renal tubular expression of epithelial Na+ channel (ENaC) is influenced by a functional rs4149601 G→A NEDD4L polymorphism. As diuretics and β-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the β-blocker or diuretic-induced blood pressure reduction and prevention of cardiovascular disease would be greater in patients with the highest ENaC expression (rs4149601 G-allele), whereas there would be no such genetically mediated differences in treatment efficacy among patients treated with the vasodilator diltiazem. METHODS: We related rs4149601 status to 6-month blood pressure reduction and risk of cardiovascular events in 5152 hypertensive patients (DBP ≥ 100 mmHg) from the Nordic Diltiazem Study (NORDIL) randomized to either β-blocker and/or diuretic-based treatment or diltiazem-based treatment. RESULTS: In patients on β-blocker or diuretic monotherapy, carriers of the G-allele had greater SBP reduction (19.5 ± 16.8 vs. 15.0 ± 19.3 mmHg, P &lt; 0.001) and DBP reduction (15.4 ± 8.3vs. 14.1 ± 8.4 mmHg, P = 0.02) and during 4.5 years of follow-up among patients randomized to β-blockers and/or diuretics, carriers of the G-allele had greater protection from cardiovascular events [relative risk (RR) = 0.52, 95% confidence interval (CI) = 0.36-0.74, P &lt; 0.001] as compared to AA homozygotes. Within the diltiazem group, there was no difference in blood pressure reduction or risk of cardiovascular events according to genotype. CONCLUSION: The functional NEDD4L rs4149601 polymorphism influences the efficacy of β-blocker and/or diuretic-based antihypertensive treatment both in terms of blood pressure reduction and cardiovascular disease protection, whereas diltiazem-based antihypertensive treatment efficacy is not influenced by this NEDD4L polymorphism.},
  author       = {Svensson, Patrik and Wahlstrand, Björn and Almgren, Peter and Dahlberg, Jonas and Fava, Cristiano and Kjeldsen, Sverre and Hedner, Thomas and Melander, Olle},
  issn         = {1473-5598},
  keyword      = {hypertension treatment,ENaC,NORDIL,pharmacogenetics},
  language     = {eng},
  number       = {2},
  pages        = {388--395},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Journal of Hypertension},
  title        = {A functional variant of the NEDD4L gene is associated with beneficial treatment response with β-blockers and diuretics in hypertensive patients.},
  url          = {http://dx.doi.org/10.1097/HJH.0b013e3283410390},
  volume       = {29},
  year         = {2011},
}