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 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.


CONCLUSIONS
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.
Department of Clinical Sciences, Lund University and Center for Emergency Medicine, Malmö University Hospital, Malmö, Sweden.
Patrik
P
Svensson-Färbom
Björn
B
Wahlstrand
Peter
P
Almgren
Jonas
J
Dahlberg
Cristiano
C
Fava
Sverre
S
Kjeldsen
Thomas
T
Hedner
Olle
O
Melander
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000368:Aged; D000483:Alleles; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics / Q000517:prevention & control; D004110:Diltiazem / Q000627:therapeutic use; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000075702:Nedd4 Ubiquitin Protein Ligases; D020641:Polymorphism, Single Nucleotide; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D014665:Vasodilator Agents / Q000627:therapeutic use
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D049993:Sodium Chloride Symporter Inhibitors; D014665:Vasodilator Agents; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; D004110:Diltiazem