. 2022 Nov;79(11):2573-2582.

doi: 10.1161/HYPERTENSIONAHA.121.18513. Epub 2022 Oct 4.

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

Brandon M Blobner¹, Annet Kirabo², Ossama B Kashlan^{3

4}, Shaohu Sheng³, Donna K Arnett⁵, Lewis C Becker⁶, Eric Boerwinkle^{7

8}, Jenna C Carlson^{9

10}, Yan Gao¹¹, Richard A Gibbs^{8

12}, Jiang He^{13

14}, Marguerite R Irvin¹⁵, Sharon L R Kardia¹⁶, Tanika N Kelly^{13

14}, Charles Kooperberg¹⁷, Stephen T McGarvey¹⁸, Vipin K Menon⁸, May E Montasser¹⁹, Take Naseri^{18

20}, Susan Redline^{21

22

23}, Alexander P Reiner¹⁷, Muagututi'a S Reupena²⁴, Jennifer A Smith¹⁶, Xiao Sun¹³, Dhananjay Vaidya^{25

26}, Karine A Viaud-Martinez²⁷, Daniel E Weeks^{9

10}, Lisa R Yanek²⁵, Xiaofeng Zhu²⁸; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium*; Ryan L Minster¹⁰, Thomas R Kleyman^{3

29

30}

Affiliations

¹ Division of Gastroenterology, Hepatology, and Nutrition (B.M.B.), University of Pittsburgh, Pittsburgh' PA.
² Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (A.K.).
³ Renal-Electrolyte Division (O.B.K., S.S., T.R.K.), University of Pittsburgh, Pittsburgh' PA.
⁴ Department of Medicine, Department of Computational and Systems Biology (O.B.K.), University of Pittsburgh, Pittsburgh' PA.
⁵ College of Public Health, University of Kentucky, Lexington' KY (D.K.A.).
⁶ GeneSTAR Research Program, Division of Cardiology, Department of Medicine (L.C.B.), Johns Hopkins University School of Medicine, Baltimore, MD.
⁷ Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston' Houston' TX (E.B.).
⁸ Human Genome Sequencing Center (E.B., R.A.G., V.K.M.), Baylor College of Medicine, Houston, TX.
⁹ Department of Biostatistics, (J.C.C., D.E.W.), University of Pittsburgh, Pittsburgh' PA.
¹⁰ Department of Human Genetics, (J.C.C., D.E.W., R.L.M.), University of Pittsburgh, Pittsburgh' PA.
¹¹ Department of Medicine, University of Mississippi Medical Center, Jackson' MS (Y.G.).
¹² Department of Molecular and Human Genetics (R.A.G.), Baylor College of Medicine, Houston, TX.
¹³ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (J.H., T.K.N., X.S.).
¹⁴ Tulane University Translational Science Institute, New Orleans, LA (J.H., T.N.K.).
¹⁵ Department of Epidemiology, University of Alabama at Birmingham' Birmingham' AL (M.R.I.).
¹⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor' MI (S.L.R.K., J.A.S.).
¹⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (C.K., A.P.R.).
¹⁸ Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI (S.T.M., T.N.).
¹⁹ Department of Medicine, University of Maryland, Baltimore' MD (M.E.M.).
²⁰ Ministry of Health, Apia, Samoa (T.N.).
²¹ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA (S.R.).
²² Harvard Medical School, Boston, MA (S.R.).
²³ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (S.R.).
²⁴ Lutia i Puava 'ae Mapu i Fagalele, Apia, Samoa (M.S.R.).
²⁵ GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine (D.V., L.R.Y.), Johns Hopkins University School of Medicine, Baltimore, MD.
²⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (D.V.).
²⁷ Illumina Laboratory Services, Illumina Inc, San Diego, CA (K.A.V.-M.).
²⁸ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH (X.Z.).
²⁹ Department of Cell Biology, (T.R.K.), University of Pittsburgh, Pittsburgh' PA.
³⁰ Department of Pharmacology and Chemical Biology, (T.R.K.), University of Pittsburgh, Pittsburgh' PA.

PMID: 36193739
PMCID: PMC9669116
DOI: 10.1161/HYPERTENSIONAHA.121.18513

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

Brandon M Blobner et al. Hypertension. 2022 Nov.

. 2022 Nov;79(11):2573-2582.

doi: 10.1161/HYPERTENSIONAHA.121.18513. Epub 2022 Oct 4.

Authors

Affiliations

¹ Division of Gastroenterology, Hepatology, and Nutrition (B.M.B.), University of Pittsburgh, Pittsburgh' PA.
² Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (A.K.).
³ Renal-Electrolyte Division (O.B.K., S.S., T.R.K.), University of Pittsburgh, Pittsburgh' PA.
⁴ Department of Medicine, Department of Computational and Systems Biology (O.B.K.), University of Pittsburgh, Pittsburgh' PA.
⁵ College of Public Health, University of Kentucky, Lexington' KY (D.K.A.).
⁶ GeneSTAR Research Program, Division of Cardiology, Department of Medicine (L.C.B.), Johns Hopkins University School of Medicine, Baltimore, MD.
⁷ Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston' Houston' TX (E.B.).
⁸ Human Genome Sequencing Center (E.B., R.A.G., V.K.M.), Baylor College of Medicine, Houston, TX.
⁹ Department of Biostatistics, (J.C.C., D.E.W.), University of Pittsburgh, Pittsburgh' PA.
¹⁰ Department of Human Genetics, (J.C.C., D.E.W., R.L.M.), University of Pittsburgh, Pittsburgh' PA.
¹¹ Department of Medicine, University of Mississippi Medical Center, Jackson' MS (Y.G.).
¹² Department of Molecular and Human Genetics (R.A.G.), Baylor College of Medicine, Houston, TX.
¹³ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (J.H., T.K.N., X.S.).
¹⁴ Tulane University Translational Science Institute, New Orleans, LA (J.H., T.N.K.).
¹⁵ Department of Epidemiology, University of Alabama at Birmingham' Birmingham' AL (M.R.I.).
¹⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor' MI (S.L.R.K., J.A.S.).
¹⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (C.K., A.P.R.).
¹⁸ Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI (S.T.M., T.N.).
¹⁹ Department of Medicine, University of Maryland, Baltimore' MD (M.E.M.).
²⁰ Ministry of Health, Apia, Samoa (T.N.).
²¹ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA (S.R.).
²² Harvard Medical School, Boston, MA (S.R.).
²³ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (S.R.).
²⁴ Lutia i Puava 'ae Mapu i Fagalele, Apia, Samoa (M.S.R.).
²⁵ GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine (D.V., L.R.Y.), Johns Hopkins University School of Medicine, Baltimore, MD.
²⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (D.V.).
²⁷ Illumina Laboratory Services, Illumina Inc, San Diego, CA (K.A.V.-M.).
²⁸ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH (X.Z.).
²⁹ Department of Cell Biology, (T.R.K.), University of Pittsburgh, Pittsburgh' PA.
³⁰ Department of Pharmacology and Chemical Biology, (T.R.K.), University of Pittsburgh, Pittsburgh' PA.

PMID: 36193739
PMCID: PMC9669116
DOI: 10.1161/HYPERTENSIONAHA.121.18513

Abstract

Background: The epithelial Na⁺ channel (ENaC) is intrinsically linked to fluid volume homeostasis and blood pressure. Specific rare mutations in SCNN1A, SCNN1B, and SCNN1G, genes encoding the α, β, and γ subunits of ENaC, respectively, are associated with extreme blood pressure phenotypes. No associations between blood pressure and SCNN1D, 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 SCNN1A and SCNN1B were associated with diastolic blood pressure and mean arterial pressure (P<0.00625). Although SCNN1D is poorly expressed in human kidney tissue, SCNN1D variants were associated with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure (P<0.00625). ENaC variants in 2 of the 4 subunits (SCNN1B and SCNN1D) were also associated with estimated glomerular filtration rate (P<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.

Keywords: ENaC (epithelial Na+ channel); arterial pressure; blood pressure; glomerular filtration rate; kidney; stroke.

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Figures

**Figure 1.. Expression of ENaC subunits in human monocytes.**
Human monocytes were exposed to a normal (150 mM) or high (190 mM) NaCl solution for 72 h, and RNA was isolated and sequenced. Normalized fragments per kilobase of transcript per million mapped reads (FPKM) are shown. Similar levels of expression of δ ENaC were seen between the two exposures (p = 0.06, unpaired Student’s t test).

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

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

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