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Genetic variation in NEDD4L, an epithelial sodium channel regulator, is associated with cardiovascular disease and cardiovascular death

Dahlberg, Jonasa,b; Sjögren, Marketaa; Hedblad, Boa; Engström, Gunnara; Melander, Ollea,b

doi: 10.1097/HJH.0000000000000044
ORIGINAL PAPERS: Genetic aspects

Objectives: We have previously shown that genetic variance in NEDD4L, a regulating protein of a sodium channel in the distal nephron, has been associated with marginally higher blood pressure and enhanced salt sensitivity. Here, we tested if the genetic NEDD4L variation previously associated with salt sensitivity is related to population blood pressure, incidence of cardiovascular disease (CVD) and mortality.

Method: We genotyped the rs4149601 A→G and rs2288774 T→C NEDD4L variants in 27 564 participants of the Malmö Diet and Cancer Study. The genotype combination previously shown to be associated with salt sensitivity (rs4149601 GG+rs2288774 CC), which was present in 9.6% of participants, was related to cross sectional blood pressure as well as to CVD incidence and mortality during a median follow-up time of 14 years using Cox regression models.

Results: Carriers of the NEDD4L salt sensitivity-associated genotype had (mean ± SEM) higher systolic (142 ± 0.4 vs. 141 ± 0.1 mmHg, P = 0.002) and diastolic (86.0 ± 0.5 vs. 85.6 ± 0.2 mmHg, P = 0.025) blood pressure and multivariate adjusted hazards ratio (95% confidence interval) of CVD 1.13 (1.02–1.25, P = 0.018), coronary events 1.20 (1.06–1.37; P = 0.005) and cardiovascular mortality 1.17 (0.99–1.37; P = 0.055) than noncarriers but there was no significant difference in the incidence of stroke and total mortality.

Conclusion: The NEDD4L salt sensitivity-associated genotype was associated with higher blood pressure, which may translate into increased risk for CVD morbidity and mortality. Interestingly, there was no association with stroke suggesting that the association is partially blood pressure independent.

aDepartment of Clinical Sciences in Malmö, Lund University

bDepartment of Internal Medicine, Skåne University Hospital, Malmö, Sweden

Correspondence to Jonas Dahlberg, Malmö, Sweden. Tel: +46 40 391209; fax: +46 40 391222; e-mail:

Abbreviations: CVD, cardiovascular disease; ENaC, amiloride-sensitive Epithelial Sodium Channel; HR, hazard ratio; MDC, Malmö Diet and Cancer study; NEDD4L, Neural precursor cell Expressed Developmentally Down regulated 4 Like; PY motif, cytoplasmic proline rich segment; TIA, transitory ischemic attacks

Received 14 April, 2012

Revised 10 September, 2013

Accepted 4 October, 2013

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