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Multidimensional exploration of blood pressure genetics and the epithelial Na⁺ channel

Blobner, Brandon M (2019) Multidimensional exploration of blood pressure genetics and the epithelial Na⁺ channel. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The epithelial Na⁺ channel (ENaC) is part of the mechanism for fine-tuning Na⁺ reabsorption and blood pressure in the distal nephron of the kidney. The ‘thumb’ domain, interacts with the pore at its base, and interacts with the ‘finger’ domain at its tip. By crosslinking the sites between the thumb and finger domains, we show that one of the finger domain cysteines in the α subunit and both of the finger domain cysteines in the γ subunit lie near the finger–thumb domain interface. We also observed functional asymmetry between the α and γ subunits: crosslinking the α subunit finger–thumb interface only inhibited ENaC currents, while crosslinking the γ subunit finger–thumb interface activated or inhibited currents in a crosslinker-length-dependent manner.
Gain-of-function or loss-of-function ENaC mutations have profound effects on renal Na⁺ reabsorption and blood pressure. While several ENaC single nucleotide variants (SNVs) with large effect sizes have been identified, the impact of rare ENaC SNVs on blood pressure has not been assessed. Using a large genomic sequencing database, TOPMed, we are able to explore the effects of rare ENaC variants sequenced from 62,784 individuals. We identified 38 SNVs that affect ENaC expression or function. Using burden tests and SKAT, we analyzed the burden of rare ENaC variants associated with blood pressure, stroke, and CKD from a subset of TOPMed studies. Our results indicate that rare ENaC variants are associated with blood pressure phenotypes.
Hypertension is a significant public health concern and affects over a quarter of adults globally. It is a risk factor for cardiovascular disease, stroke, and kidney disease; therefore, it is a leading contributor to mortality. 901 blood pressure associated loci have been identified in the literature; yet, these variants only explain 11% of blood pressure variance. We have performed GWAS for five blood pressure traits in a population of 3,400 individuals from Samoa. Exploring blood pressure genetics through GWAS in this population isolate may provide additional insights into the mechanisms controlling blood pressure that are unseen in other populations as well as how far reaching some aspects of shared blood pressure genetics can be.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Blobner, Brandon Mbmblobner@gmail.combmb83
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKleyman, Thomas
Committee MemberKashlan, Ossama Bobk2@pitt.eduobk2
Committee MemberMinster, Ryan
Committee MemberKammerer, Candace Mcmk3@pitt.educmk3
Date: 30 January 2019
Date Type: Publication
Defense Date: 21 August 2018
Approval Date: 30 January 2019
Submission Date: 21 November 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 187
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: blood pressure genetics ENaC sodium ion transport
Related URLs:
Date Deposited: 30 Jan 2019 18:45
Last Modified: 01 Jan 2024 06:15


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