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

TitleRare Variants in Genes Encoding Subunits of the Epithelial Na Channel Are Associated With Blood Pressure and Kidney Function.
Publication TypeJournal Article
Year of Publication2022
AuthorsBlobner, BM, Kirabo, A, Kashlan, OB, Sheng, S, Arnett, DK, Becker, LC, Boerwinkle, E, Carlson, JC, Gao, Y, Gibbs, RA, He, J, Irvin, MR, Kardia, SLR, Kelly, TN, Kooperberg, C, McGarvey, ST, Menon, VK, Montasser, ME, Naseri, T, Redline, S, Reiner, AP, Reupena, M'aS, Smith, JA, Sun, X, Vaidya, D, Viaud-Martinez, KA, Weeks, DE, Yanek, LR, Zhu, X, Minster, RL, Kleyman, TR
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium*
JournalHypertension
Volume79
Issue11
Pagination2573-2582
Date Published2022 Nov
ISSN1524-4563
KeywordsBlood Pressure, Epithelial Sodium Channels, Humans, Kidney, Phenotype, Sodium
Abstract

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 (

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

DOI10.1161/HYPERTENSIONAHA.121.18513
Alternate JournalHypertension
PubMed ID36193739
PubMed Central IDPMC9669116
Grant ListR01 HL087698 / HL / NHLBI NIH HHS / United States
P30 DK079307 / DK / NIDDK NIH HHS / United States
R01 HL133040 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 NR002241 / NR / NINR NIH HHS / United States
R01 HG011052 / HG / NHGRI NIH HHS / United States
U01 HL072518 / HL / NHLBI NIH HHS / United States
R01 HL147818 / HL / NHLBI NIH HHS / United States
T32 DK063922 / DK / NIDDK NIH HHS / United States
R01 HL087263 / HL / NHLBI NIH HHS / United States
R01 HL049762 / HL / NHLBI NIH HHS / United States
R01 HL046380 / HL / NHLBI NIH HHS / United States
M01 RR000052 / RR / NCRR NIH HHS / United States
R35 HL135816 / HL / NHLBI NIH HHS / United States
U01 HL072507 / HL / NHLBI NIH HHS / United States
R01 HL090682 / HL / NHLBI NIH HHS / United States
T32 DK061296 / DK / NIDDK NIH HHS / United States
R01 DK125439 / DK / NIDDK NIH HHS / United States
R01 HL144941 / HL / NHLBI NIH HHS / United States
R01 HL113338 / HL / NHLBI NIH HHS / United States
R01 HL112064 / HL / NHLBI NIH HHS / United States
R01 HL093093 / HL / NHLBI NIH HHS / United States
R01 HL056205 / HL / NHLBI NIH HHS / United States
R03 HL155041 / HL / NHLBI NIH HHS / United States
K01 HL130497 / HL / NHLBI NIH HHS / United States
R01 HL055673 / HL / NHLBI NIH HHS / United States
R01 HL071025 / HL / NHLBI NIH HHS / United States
R01 DK098204 / DK / NIDDK NIH HHS / United States

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