Rare Variants in Genes Encoding Subunits of the Epithelial Na Channel Are Associated With Blood Pressure and Kidney Function.

BACKGROUND

The epithelial Na channel (ENaC) is intrinsically linked to fluid volume homeostasis and blood pressure. Specific rare mutations in , , and , genes encoding the α, β, and γ subunits of ENaC, respectively, are associated with extreme blood pressure phenotypes. No associations between blood pressure and , which encodes the δ subunit of ENaC, have been reported. A small number of sequence variants in ENaC subunits have been reported to affect functional transport in vitro or blood pressure. The effects of the vast majority of rare and low-frequency ENaC variants on blood pressure are not known.

METHODS

We explored the association of low frequency and rare variants in the genes encoding ENaC subunits, with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure. Using whole-genome sequencing data from 14 studies participating in the Trans-Omics in Precision Medicine Whole-Genome Sequencing Program, and sequence kernel association tests.

RESULTS

We found that variants in and were associated with diastolic blood pressure and mean arterial pressure (<0.00625). Although is poorly expressed in human kidney tissue, variants were associated with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure (<0.00625). ENaC variants in 2 of the 4 subunits ( and ) were also associated with estimated glomerular filtration rate (<0.00625), but not with stroke.

CONCLUSIONS

Our results suggest that variants in extrarenal ENaCs, in addition to ENaCs expressed in kidneys, influence blood pressure and kidney function.