Physiological interaction between ADD1 and WNK1-NEDD4L pathways on sodium related blood pressure regulation

The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants
in the genes for alpha-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 (n344 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.