Primary aldosteronism affects up to 10% of hypertensive patients and is responsible for treatment resistance and increased cardiovascular risk. Here we perform a genome-wide association study in a discovery cohort of 562 cases and 950 controls and identify three main loci on chromosomes 1, 13 and X; associations on chromosome 1 and 13 are replicated in a second cohort and confirmed by a meta-analysis involving 1162 cases and 3296 controls. The association on chromosome 13 is specific to men and stronger in bilateral adrenal hyperplasia than aldosterone producing adenoma. Candidate genes located within the two loci, CASZ1 and RXFP2, are expressed in human and mouse adrenals in different cell clusters. Their overexpression in adrenocortical cells suppresses mineralocorticoid output under basal and stimulated conditions, without affecting cortisol biosynthesis. Our study identifies the first risk loci for primary aldosteronism and highlights new mechanisms for the development of aldosterone excess.
Context Aldosterone-producing adenomas (APA) are a common cause of primary aldosteronism. Despite the discovery of somatic mutations in APA and characterization of multiple factors regulating adrenal differentiation and function, the sequence of events leading to APA formation remains to be determined. Objective We investigated the role of Wnt/β-catenin and ACTH signaling, as well as elements of paracrine regulation of aldosterone biosynthesis in adrenals with APA and their relationship to intratumoral heterogeneity and mutational status. Design We analyzed expression of CYP11B2, CYP17A1, β-catenin, MC2R, pCREB, Tryptase, S100, CD34 by multiplex immunofluorescence and IHC guided RT-qPCR. Setting 11 adrenals with APA and one with micronodular hyperplasia from patients with PA were analysed. Main Outcome Measure(s) Localization of CYP11B2, CYP17A1, β-catenin, MC2R, pCREB, Tryptase, S100, CD34 in APA and aldosterone producing cell clusters (APCC). Results Immunofluorescence revealed abundant mast cells and a dense vascular network in APA, independent of mutational status. Within APA, mast cells were localized in areas expressing CYP11B2 and were rarely co-localized with nerve fibers, suggesting that their degranulation is not controlled by innervation. In these same areas, ß-catenin was activated, suggesting a zona glomerulosa cell identity. In heterogeneous APA with KCNJ5 mutations, MC2R and VEGFA expression was higher in areas expressing CYP11B2. A similar pattern was observed in APCC, with high expression of CYP11B2, activated β-catenin, and numerous mast cells. Conclusions Our results suggest that aldosterone producing structures in adrenals with APA share common molecular characteristics and cellular environment, despite different mutation status, suggesting common developmental mechanisms.
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