Key result
Combined ADD1, WNK1, and NEDD4L variants linked to altered sodium handling and thiazide BP response.
Why the study?
Variants in the genes ADD1, WNK1, and NEDD4L have been associated with increased blood pressure, but findings have been inconsistent, possibly due to physiological interactions between these gene variants.
Do combined variants in the ADD1, WNK1, and NEDD4L genes affect sodium-related blood pressure regulation and response to thiazides?
Observational
Do combined variants in the ADD1, WNK1, and NEDD4L genes affect sodium-related blood pressure regulation and response to thiazides?
p-value: p=0.009 to 0.044
Combined genetic variants in ADD1, WNK1, and NEDD4L significantly influence renal sodium handling, blood pressure, and the antihypertensive response to thiazide diuretics.
May support genotype-guided thiazide selection; leaves open prospective validation before clinical use.
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 (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.
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Manunta et al. (2008) conducted an observational in Blood pressure regulation. ADD1 Trp, WNK1 GG, and Nedd4L GA+AA variant combination vs. Other genotypes was evaluated on Renal Na handling, acute BP response to saline infusion, BP lowering after thiazide treatment, and nocturnal systolic BP (p=0.009 to 0.044). The combination of ADD1 Trp, WNK1 GG, and Nedd4L GA+AA variants significantly influenced renal sodium handling (P=0.009), acute BP response to saline (P=0.021), and thiazide BP lowering (P=0.008).
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