Genetic Causes of Endocrine Hypertension in Black Americans

PROJECT SUMMARY/ABSTRACT Primary aldosteronism (PA) is not only the most common adrenal disorder but also the most common cause of endocrine hypertension. PA is characterized by renin-independent adrenal aldosterone production that results in excessive mineralocorticoid receptor activation which eventually leads to hypertension. PA is also associated with higher rates of cardiovascular morbidity and mortality compared to blood pressure-matched essential hypertension. Despite its high prevalence, PA is vastly under-recognized in the hypertensive population preventing proper medical therapy for these patients. Over the past decades, it has become clear that PA results, in part, from the disruption of adrenal cell calcium homeostasis leading to increased aldosterone synthase (CYP11B2) expression and aldosterone production. The introduction of next-generation sequencing (NGS) has provided important clues to the pathogenesis of PA and has defined a series of somatic mutations in genes that encode proteins impacting intracellular calcium levels, including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CLCN2 and SLC30A1 (aldosterone-driver gene mutations). Research focused on defining the genetic causes of PA in Black Americans, however, is limited despite the high prevalence of salt-sensitive hypertension, and their higher susceptibility to hyperaldosteronism and cardiovascular mortality. The overall objectives of this proposal are: 1) to define the spectrum of aldosterone-driver PA somatic mutations in Black American patients, and 2) to identify targeted therapeutics that block mutation-driven aldosterone production in endocrine hypertension. Two specific aims have been designed to address critical gaps in the care of Black American PA patients. • In Aim 1, we will probe the hypothesis that Black American PA adrenals harbor novel somatic mutations that cause aldosterone excess via increased intracellular calcium and CYP11B2 activity. We will implement CYP11B2 immunohistochemistry-guided NGS to identify aldosterone- driver somatic mutations Black American PA adrenals. We will then define the disease-causing mechanisms for novel aldosterone-driver somatic mutations using genetically engineered adrenal cell lines. • In Aim 2, we will probe the hypothesis that in Black Americans, PA is caused by aldosterone-driver mutations that can be targeted by the currently available calcium channel inhibitors (CCIs). We will develop genetically engineered adrenal cell lines expressing the major aldosterone-driver mutations found in Black Americans with PA. This will be followed by testing these mutation-expressing cell lines to determine the efficacy of CCIs to inhibit mutation-driven aldosterone production in Black Americans with PA. The proposed research would significantly improve our understanding of the molecular mechanisms causing PA in Black Americans and provide foundational information needed for the future development of available targeted therapeutics to treat PA in Black Americans.