# A Novel Locus in the Regulation of Human Water Balance

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2021 · —

## Abstract

Hyponatremia, a relative excess of total body water, is the most frequently encountered electrolyte
abnormality. Although some instances are readily attributed to heart, liver, or kidney failure, many are
unexplained. Water excess causes confusion, lethargy, seizures, and death. Even mild hyponatremia
causes reversible deficits in coordination and cognition.
The applicant's preliminary data show that the plasma sodium concentration is highly individual (i.e.,
relatively constant in any one individual) and is heritable. In a meta-genome-wide association study for
common gene variants that influence water balance, the applicant and co-workers identified variants in
a gene not previously suspected of playing a role in whole-body water balance, but exhibiting extremely
high biological plausibility. The lead variant affects an intronic enhancer within the gene. Remarkably, a
second association locus codes for the transcription factor predicted to bind this enhancer. Therefore,
the overarching objective of this proposal is to demonstrate the centrality of this enhancer region, this
gene variant, and this gene to systemic osmoregulation using a combination of in vitro and whole-
animal models.
In Aim 1, the functional significance (i.e., osmotic responsiveness) of the enhancer region and allele-
specific effects will be probed through reporter gene and DNA binding assays. In Aim 2, the effect of
downregulating this gene upon osmotic phenotype will be tested in cultured cells natively expressing
the protein. In Aim 3, transgenic mouse models will be used to test the importance of this gene to
systemic water balance under basal conditions, and in response to physiological maneuvers designed
to perturb water balance.

## Key facts

- **NIH application ID:** 10047697
- **Project number:** 5I01BX003449-04
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** DAVID M COHEN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047697

## Citation

> US National Institutes of Health, RePORTER application 10047697, A Novel Locus in the Regulation of Human Water Balance (5I01BX003449-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047697. Licensed CC0.

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