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(Hypertension. 2008;52:366.)
© 2008 American Heart Association, Inc.

Original Articles

Physiological Interaction Between -Adducin and WNK1-NEDD4L Pathways on Sodium-Related Blood Pressure Regulation

Paolo Manunta; Gail Lavery; Chiara Lanzani; Peter S. Braund; Marco Simonini; Claire Bodycote; Laura Zagato; Simona Delli Carpini; Cristina Tantardini; Elena Brioni; Giuseppe Bianchi; Nilesh J. Samani

From the San Raffaele Scientific Institute (P.M., C.L., M.S., L.Z., S.D.C., C.T., E.B., G.B.), Division of Nephrology, Dialysis, and Hypertension, Università "Vita-Salute" San Raffaele, Chair of Nephrology, Milan, Italy; and the Department of Cardiovascular Sciences (G.L., P.S.B., C.B., N.J.S.), University of Leicester, Leicester, United Kingdom.

Correspondence to Paolo Manunta, Division of Nephrology, Dialysis, and Hypertension, University "Vita-Salute" San Raffaele Hospital, Via Olgettina 60, 20132 Milan, Italy. E-mail manunta.paolo{at}hsr.it or Nilesh J. Samani, Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, United Kingdom. E-mail: njs@le.ac.uk

The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants in the genes for -adducin (ADD1), WNK1, and NEDD4L, which all regulate renal sodium absorption, have been associated with increased BP. However, findings have been inconsistent. We tested whether this is because of physiological interactions between the effects of variants in these genes. We assessed the single and combined effects of the ADD1 (Gly460Trp), WNK1 (rs880054 A/G), and NEDD4L (rs4149601 G/A) polymorphisms on renal and BP response to an acute Na load (n=344 subjects), BP decrease after 1 month of treatment with 12.5 mg of hydrochlorothiazide (n=193), and ambulatory 24-hour BP (n=690). Individually, the variants showed modest effects on some of the studied phenotypes. We found the ADD1 Trp allele to be permissive for the effects of variants of the other genes. In combination, the same variants (ADD1 Trp/WNK1 GG/Nedd4L GA+AA) showed a consistent effect on renal Na handling (P=0.009) and acute BP response to a saline infusion (P=0.021), BP lowering after thiazide treatment (P=0.008), and nocturnal systolic BP (P=0.044). Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. Relatively common alleles in the ADD1, WNK1, and NEDD4L genes when present in combination may have significant effects on renal sodium handling, BP, and antihypertensive response to thiazides.

Key Words: hypertension • genetic • sodium transport • kidney • blood pressure • tubular • renal