A functional variant of the NEDD4L gene is associated with... : Journal of Hypertension (original) (raw)

Original papers: Therapeutic aspects

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

Svensson-Färbom, Patrika; Wahlstrand, Björnb; Almgren, Petera; Dahlberg, Jonasa; Fava, Cristianoa,d; Kjeldsen, Sverrec; Hedner, Thomasb; Melander, Ollea

aDepartment of Clinical Sciences, Lund University and Center for Emergency Medicine, Malmö University Hospital, Malmö, Sweden

bDepartment of Clinical Pharmacology, Sahlgrenska University Hospital, Göteborg, Sweden

cUllevaal University Hospital, University of Oslo, Oslo, Norway

dDepartment of Biomedical and Surgical Sciences, University of Verona, Italy

Received 12 March, 2010

Revised 24 September, 2010

Accepted 27 September, 2010

Correspondence to Olle Melander, Department of Clinical Sciences, Clinical Research Center, Entrance 72, Building 91, floor 12, Malmö University Hospital, SE-205 02 Malmö, Sweden Tel: +46 40 391209; fax: +46 40 391222; e-mail: [email protected]

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 < 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.