Identify mechanisms linking proliferative predisposition and aldosterone excess in APA

Identify the molecular mechanisms that link an initial proliferative predisposition affecting adrenal cortex homeostasis (e.g., genetic risk alleles for primary aldosteronism) with a second hit that drives autonomous aldosterone production (e.g., somatic KCNJ5 mutations), explaining how these two models integrate in aldosterone-producing adenoma pathogenesis.

Background

The authors propose that APA formation may require two cooperating events: a proliferative predisposition (supported by PA risk alleles identified in GWAS that modulate adrenal homeostasis and cell proliferation) and a second mutation that increases intracellular calcium and aldosterone (such as KCNJ5).

While these models are not mutually exclusive, the specific molecular connections between proliferative drivers and aldosterone-producing mutations have not been delineated. Elucidating these mechanisms would clarify APA etiology and suggest targeted interventions.