Update on the Genetics of Primary Aldosteronism and Aldosterone-Producing Adenomas

Curr Cardiol Rep. 2022 Sep;24(9):1189-1195. doi: 10.1007/s11886-022-01735-z. Epub 2022 Jul 16.

Abstract

Purpose of the review: Primary aldosteronism (PA) is the leading cause of secondary hypertension, accounting for over 10% of patients with high blood pressure. It is characterized by autonomous production of aldosterone from the adrenal glands leading to low-renin levels. The two most common forms arise from bilateral adrenocortical hyperplasia (BAH) and aldosterone-producing adenoma (APA). We discuss recent discoveries in the genetics of PA.

Recent findings: Most APAs harbor variants in the KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 genes. With the exception of β-catenin (CTNNB1), all other causative genes encode ion channels; pathogenic variants found in PA lead to altered ion transportation, cell membrane depolarization, and consequently aldosterone overproduction. Some of these genes are found mutated in the germline state (CYP11B2, CLCN2, KCNJ5, CACNA1H, and CACNA1D), leading then to familial hyperaldosteronism, and often BAH rather than single APAs. Several genetic defects in the germline or somatic state have been identified in PA. Understanding how these molecular abnormalities lead to excess aldosterone contributes significantly to the elucidation of the pathophysiology of low-renin hypertension. It may also lead to new and more effective therapies for this disease acting at the molecular level.

Keywords: Aldosterone-producing adenoma; Hypertension; Primary aldosteronism; Resistant hypertension.

Publication types

  • Review

MeSH terms

  • Adenoma* / complications
  • Adenoma* / genetics
  • Adenoma* / metabolism
  • Adrenal Cortex Neoplasms* / complications
  • Adrenal Cortex Neoplasms* / genetics
  • Adrenal Cortex Neoplasms* / metabolism
  • Adrenal Gland Neoplasms* / complications
  • Adrenocortical Adenoma* / complications
  • Adrenocortical Adenoma* / genetics
  • Adrenocortical Adenoma* / metabolism
  • Aldosterone / metabolism
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • Humans
  • Hyperaldosteronism* / complications
  • Hyperaldosteronism* / genetics
  • Hypertension* / genetics
  • Mutation
  • Renin
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Sodium-Potassium-Exchanging ATPase / metabolism

Substances

  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • KCNJ5 protein, human
  • Aldosterone
  • Renin
  • Sodium-Potassium-Exchanging ATPase