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

Svensson, Patrik; Wahlstrand, Björn; Almgren, Peter; Dahlberg, Jonas; Fava, Cristiano; Kjeldsen, Sverre; Hedner, Thomas; Melander, Olle

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

Mark

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)

Please use this url to cite or link to this publication: https://lup.lub.lu.se/record/1732300

author

Svensson, Patrik ^LU ; Wahlstrand, Björn ; Almgren, Peter ^LU ; Dahlberg, Jonas ^LU ; Fava, Cristiano ^LU ; Kjeldsen, Sverre ; Hedner, Thomas and Melander, Olle ^LU

organization

publishing date

2011

type

Contribution to journal

publication status

published

subject

Cardiac and Cardiovascular Systems

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
pmid:21052022

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

2016-04-01 13:54:49

date last changed

2024-03-13 11:12:18

@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}},
  keywords     = {{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}},
  doi          = {{10.1097/HJH.0b013e3283410390}},
  volume       = {{29}},
  year         = {{2011}},
}

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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.