# The Genetics of Primary Aldosteronism

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $387,500

## Abstract

Project Summary/Abstract 
Primary aldosteronism (PA) is the most common cause of secondary hypertension, representing a significant
risk factor for cardiovascular, cerebrovascular events and chronic kidney disease. PA accounts for up to 24%
of all refractory hypertension and its prevalence is estimated to be as high as 1 in 50 people. In normal
physiology adrenal aldosterone production is tightly regulated by angiotensin II and potassium levels. In PA
aldosterone, at least in part, escapes these regulatory mechanisms.
35% of PA are caused by unilateral adenomas and recent research has focused on somatic mutations causing
aldosterone production in these tumors, including mutations in a potassium channel (KCNJ5), Na-K ATPase
(ATP1A1), Ca ATPase (ATP2B3) and calcium channel (CACNA1D). Mutations in these genes are believed to
induce membrane depolarization and increase in calcium influx leading to increased CYP11B2 transcription
and ultimately aldosterone production.
The majority (65%) of PA is caused by idiopathic hyperaldosteonism (IHA), with both both adrenal glands
being the source of aldosterone. Germline mutations (e.g. CYP11B2/CYP11B1 cross-over, KCNJ5,
CACNA1D) explain less than ~2% of all IHA cases.
The current proposal aims to define additional constitutional genetic mutations as causes for IHA. In
preliminary analyses we have identified several mutations in candidate genes, particularly membrane localized
ion channels and ATPases. The hypothesis is that dominantly inherited mutations can cause IHA or at least
serve as a risk factor for the disease. Aim 1 is designed to functionally characterize the effect of the mutations
on electrophysiology, intracellular signaling and aldosterone production in adrenocortical cells. Aim 2 will
explore the role of the candidate genes in apparently sporadic cases of IHA by targeted gene sequencing. Aim
3 will explore the role of the described mutations as a somatic event causing development of adenomas.
The results of this study will lead to improvement of our understanding of the adrenal pathophysiology that
underlies PA, improve the diagnosis of PA and will open new routes of a targeted therapy of PA in the future.

## Key facts

- **NIH application ID:** 9921463
- **Project number:** 5R01HL130106-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Tobias Else
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921463

## Citation

> US National Institutes of Health, RePORTER application 9921463, The Genetics of Primary Aldosteronism (5R01HL130106-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9921463. Licensed CC0.

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