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

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.