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.