title: A functional variant of NEDD4L is associated with hypertension, antihypertensive response, and orthostatic hypotension.
abstract: NEDD4L is involved in the regulation of plasma volume and blood pressure by controlling cell surface expression of the kidney epithelial Na(+) channel. Previously, the cryptic splice variant rs4149601(G/A) A allele of NEDD4L, generating isoform I, was estimated to decrease blood pressure by downregulating Na(+) reabsorption. However, a recent functional study showed that isoform I should lead to abnormal Na(+) reabsorption increases by antagonistically downregulating epithelial Na(+) channel activities. To determine whether the variant rs4149601 A allele is a risk factor for hypertension, has an impact on the antihypertensive response to hydrochlorothiazide, and is associated with orthostatic hypotension, we performed a case-control study of hypertension (n=1686), a 4-week clinical trial (n=542), and a case-control study of orthostatic hypotension (n=793) in Chinese subjects. We found that the A allele was significantly associated with hypertension after appropriate adjustment (odds ratio: 1.39; 95% CI: 1.13 to 1.72; P=0.002). The blood pressure reduction in A carriers after hydrochlorothiazide treatment was greater than that in GG carriers, with differences of 6.1 mm Hg (P=0.009) in systolic blood pressure and 2.7 mm Hg (P=0.027) in diastolic blood pressure. The A allele was significantly associated with orthostatic hypotension after adjustment for cardiovascular risk factors (odds ratio: 0.68; 95% CI: 0.48 to 0.98; P=0.039). In conclusion, rs4149601 is a genetic risk factor for hypertension and a protective factor against orthostatic hypotension in hypertensive subjects, and the antihypertensive response to hydrochlorothiazide is more sensitive in A allele carriers than in GG carriers. Consequently, the A allele may be a useful marker for predicting hypertension, orthostatic hypotension, and antihypertensive response to hydrochlorothiazide.
authors.affiliation: Hypertension Division, FuWai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Luo
authors.forename: Yibo
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Xianliang
authors.initials: X
authors.lastname: Zhou
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
mesh_terms: D000368:Aged; D000483:Alleles; D015415:Biomarkers; D016022:Case-Control Studies; D004232:Diuretics / Q000627:therapeutic use; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics*; D007024:Hypotension, Orthostatic / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D000075702:Nedd4 Ubiquitin Protein Ligases; D012307:Risk Factors; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D015415:Biomarkers; D004232:Diuretics; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D006852:Hydrochlorothiazide; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases