Common variants in epithelial sodium channel genes contribute to salt sensitivity of blood pressure: The GenSalt study

Abstract

Background: Rare mutations of the epithelial sodium channel (ENaC) lead to mendelian forms of salt-sensitive hypertension or salt-wasting hypotension. We aimed to examine the association between common variants in the ENaC genes and salt sensitivity of blood pressure (BP).

Methods and results: A total of 1906 Han Chinese participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, which includes a 7-day low-sodium intake (51.3 mmol sodium/d) followed by a 7-day high-sodium intake (307.8 mmol sodium/d). Nine BP measurements were obtained at baseline and each intervention period using a random-zero sphygmomanometer. Single-nucleotide polymorphisms, both tagging and functional, from the 3 ENaC subunits, α, β, and γ (SCNN1A, SCNN1B, and SCNN1G), were genotyped. Multiple common single-nucleotide polymorphisms in SCNN1G were significantly associated with BP response to low-sodium intervention (rs4073930, P=1.7×10(-5); rs4073291, P=1.1×10(-5); rs7404408, P=1.9×10(-5); rs5735, P=3.0×10(-4); rs4299163, P=0.004; and rs4499238, P=0.002) even after correcting for multiple testing. For example, under an additive model, the minor allele G of SNP rs4073291 was associated with 1.33 mm Hg lower systolic BP reduction during low-sodium intervention.

Conclusions: This large dietary sodium intervention study indicates that common variants of ENaC subunits may contribute to the variation of BP response to dietary sodium intake. Future studies are warranted to confirm these findings in an independent population and to identify functional variants for salt sensitivity.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00721721.

Figure 1

The log P values for the association between 46 single nucleotide polymorphisms of SCNN1A (a), SCNN1B (b), and SCNN1G (c) genes and blood pressure responses to low- and high-sodium interventions. The horizontal dash line indicates P value of 0.05. ΔSBP_BL, systolic BP changes from baseline to low-sodium intervention; ΔDBP_BL, diastolic BP changes from baseline to low-sodium intervention; ΔSBP_LH, systolic BP changes from low- to high-sodium intervention; ΔDBP_LH, diastolic BP changes from low- to high-sodium intervention.