Genotypes and Phenotypes
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See related article, pp 129–136
Primary aldosteronism (PA), which can be detected by aldosterone-to-renin ratio in its great majority, has come to be conceived as the most frequent form of secondary hypertension constituting ≈5% to 10% of unselected hypertension. PA is also clinically known to harbor relatively higher incidences of cardiovascular events and complications. As Funder1 commented, 2 recent major breakthroughs in the research fields of PA were summarized as follows. The first one was the demonstration of much higher prevalence of PA as described earlier, and, in particular, stress-induced but undiagnosed patients of hyperaldosteronism could be present among those diagnosed with essential hypertension in general population.2
The second was the development of recent biological and pathological findings, which have indeed shed enormous insights into long studied exploration of the origins of aldosterone-producing adenomas (APAs). In particular, the sophisticated approaches using next-generation sequencing did make it possible to identify various patterns of somatic mutations associated with autonomous aldosterone overproduction in APAs. These somatic mutations occur in the genes encoding the several kinds of ion channels involved in aldosterone biosynthesis, including KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1. In particular, those of KCNJ5, encoding the inward rectifier potassium channel, were the first identified and most prevalent one associated with APA, resulting in the persistent depolarization of the cell membrane and subsequently promoting aldosterone biosynthesis. At this juncture, more than one third of APAs are considered to harbor KCNJ5 mutations, especially in East Asian patients.3 These mutations frequently occur in the specific areas of the gene, known as hot spots, namely G151R and L168R.4 Of further particular interest, KCNJ5 somatic mutation was only detected in APA but by no means in aldosterone-producing cell clusters frequently identified in the nonpathological adrenal cortex.5 However, …