Aldosterone is a key cardiovascular hormone in the development of hypertension and in the evolution of heart failure. Recent studies have suggested that Primary Aldosteronism may be present around 10% of patients with high blood pressure, although the precise definition of the syndrome remains uncertain. Nevertheless, it is clear that dysregulation of aldosterone production is a common clinical phenotype in cardiovascular disease. The majority of patients with aldosterone excess do not have solitary adrenal adenomas.
We previously showed that a number of adrenal steroid phenotypes, including aldosterone secretion, were heritable, indicating that adrenal steroid synthesis was subject to genetic regulation. We have focused on the genes encoding aldosterone synthase (CYP11B2) and 11-beta hydroxylase (CYP11B1); we have demonstrated that polymorphic variation in CYP11B2 was associated with hypertension, particularly with increased aldosterone production. However, the key biochemical phenotype is that of altered efficiency of 11β hydroxylation consistent with genetic variation in CYP11B1. We have now identified common haplotypes across the CYP11B2/CYP11B1 locus and have demonstrated that variation in 11β hydroxylation relates to polymorphic variants in the promoter region of CYP11B1. In vitro studies show that these variants have a functional effect on gene expression.
We suggest that there is a long-term disregulation of adrenal steroid synthesis in subjects with genetic variation at CYP11B1 and CYP11B2. This leads to a chronic minor increase in ACTH drive to the adrenal cortex that results, in susceptible subjects, in relative aldosterone excess. Thus, Primary Aldosteronism may be an evolving phenotype over many years that reflects an interaction between a common genetic predisposition and appropriate environmental conditions.