期刊
JOURNAL OF HYPERTENSION
卷 29, 期 2, 页码 388-395出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0b013e3283410390
关键词
ENaC; hypertension treatment; NORDIL; pharmacogenetics
资金
- Swedish Medical Research Council
- Swedish Heart and Lung Foundation
- Medical Faculty of Lund University
- LUA/ALF from the Sahlgrenska Academy at Goteborg University
- Malmo University Hospital
- Albert Pahlsson Research Foundation
- Crafoord Foundation
- Ernhold Lundstroms Research Foundation
- Region Skane
- King Gustaf V and Queen Victoria Foundation
- Lennart Hanssons Memorial Fund
- Marianne and Marcus Wallenberg Foundation
- InGenious HyperCare (European Union, Network of Excellence)
- Hulda and Conrad Mossfelt Foundation
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 beta-blockers inhibit renal sodium reabsorption and renin release, respectively, we hypothesized that the beta-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 beta-blocker and/or diuretic-based treatment or diltiazem-based treatment. Results In patients on beta-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 b-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 beta-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. J Hypertens 29:388-395 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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