A Functional Variant Of NEDD4L Is Associated With Hypertension, Antihypertensive Response And Orthostatic Hypotension

The epithelial Na+ channel (ENaC)-NEDD4L-proteasome system plays an important role in blood pressure (BP) regulation. NEDD4L is the key link of this system. It is involved in the regulation of plasma volume and blood pressure by controlling cell surface expression of the kidney epithelial Na+ channel. Owing to the importance of NEDD4L for Na+ homeostasis, mutations in NEDD4L may be responsible for BP phenotypes. A frameshift mutation of NEDD4L, rs4149601 (G/A) results in premature truncation of the NEDD4L protein, Previously, the cryptic splice variant rs4149601(G/A) of NEDD4L, generating isoform I, was estimated to decrease blood pressure by downregulating Na+ reabsorption. To determine whether the variant rs4149601 A allele is a risk factor for hypertension, whether it has an impact on the antihypertensive response to hydrochlorothiazide and 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, respectively.We found that the A allele was significantly associated with hypertension after appropriate adjustment (OR,1.39; 95% CI,1.13-1.72; P=0.002). The blood pressure reduction was greater in A carriers after hydrochlorothiazide treatment than in GG carriers, with differences of 6.1 mmHg (P=0.009) in SBP and 2.7 mmHg (P=0.027) in DBP. The A allele was significantly associated with orthostatic hypotension after adjustment for cardiovascular risk factors (OR,0.68; 95% CI,0.48-0.98; P=0.039).In conclusion, rs4149601 is a genetic risk factor for hypertension, 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.