RECENT FINDINGS: KCNJ5, ATP1A1, ATP2B3, CACNA1D, CTNNB1, and CACNA1H mutations are causal of primary aldosteronism. ARMC5 may cause bilateral lesions resulting in primary aldosteronism.LGR5, DACH1, and neuron-specific proteins are highly expressed in the zona glomerulosa and regulate aldosterone production.
SUMMARY: Most mutations causing primary aldosteronism are in genes encoding cation channels or pumps, leading to increased calcium influx. Genotype-phenotype analyses identified two broad subtypes of aldosterone-producing adenomas (APAs), zona fasciculata-like and zona glomerulosa-like, and the likelihood of under-diagnosed zona glomerulosa-like APAs because of small size. Zona fasciculata-like APAs are only associated with KCNJ5 mutations, whereas zona glomerulosa-like APAs are associated with mutations in ATPase pumps, CACNA1D, and CTNNB1. The frequency of APAs, and the multiplicity of causal mutations, suggests a pre-existing drive for these mutations. We speculate that these mutations are selected for protecting against tonic inhibition of aldosterone in human zona glomerulosa, which express genes inhibiting aldosterone production.
METHODS: A systematic search was conducted on PubMed, EBSCOHost, and Web of Science. We identified 22 casecontrol studies that matched our inclusion and exclusion criteria. Information such as study characteristics, genetic polymorphisms associated with SLE, and organ manifestations was extracted and reported in this review.
RESULTS: In total, 30 polymorphisms in 16 genes were found to be associated with SLE among Asians. All included polymorphisms also reported associations with various SLE clinical features. The association of rs1234315 in TNFSF4 linking to SLE susceptibility (P=4.17x10-17 OR=1.45 95% CI=1.34-1.59) and musculoskeletal manifestation (P=3.35x10-9, OR=1.37, 95%CI= 1.23-1.51) might be the most potential biomarkers to differentiate SLE between Asian and other populations. In fact, these associated genetic variants were found in loci that were implicated in immune systems, signal transduction, gene expression that play important roles in SLE pathogenesis.
DISCUSSIONS AND CONCLUSIONS: This review summarized the potential correlation between 30 genetic polymorphisms associated with SLE and its clinical manifestations among Asians. More efforts in dissecting the functional implications and linkage disequilibrium of associated variants may be required to validate these findings.
OBJECTIVES: This study aimed to provide a personalized surgical recommendation that enables more confidence in advising patients to pursue surgical treatment.
METHODS: We enrolled 328 patients with uPA harboring KCNJ5 mutations (n = 158) or not (n = 170) who had undergone adrenalectomy. Eighty-seven features were collected, including demographics, various blood and urine test results, and clinical comorbidities. We designed 2 versions of the prediction model: one for institutes with complete blood tests (full version), and the other for institutes that may not be equipped with comprehensive testing facilities (condensed version).
RESULTS: The results show that in the full version, the Light Gradient Boosting Machine outperformed other classifiers, achieving area under the curve and accuracy values of 0.905 and 0.864, respectively. The Light Gradient Boosting Machine also showed excellent performance in the condensed version, achieving area under the curve and accuracy values of 0.867 and 0.803, respectively.
CONCLUSIONS: We simplified the preoperative diagnosis of KCNJ5 mutations successfully using machine learning. The proposed lightweight tool that requires only baseline characteristics and blood/urine test results can be widely applied and can aid personalized prediction during preoperative counseling for patients with uPA.
DESIGN: We instituted a questionnaire-based survey to specialists managing PA, assessing the availability and affordability of investigations and treatment. Population and income status data were taken from the national census and registries.
RESULTS: Nine ASEAN country members (48 respondents) participated. While screening with aldosterone-renin-ratio is performed in all countries, confirmatory testing is routinely performed in only six countries due to lack of facilities and local assays, and cost constraint. Assays are only locally available in four countries, and some centers have a test turnaround time exceeding three weeks. In seven countries (combined population of 442 million), adrenal vein sampling (AVS) is not routinely performed due to insufficient radiological facilities or trained personnel, and cost constraint. Most patients have access to adrenalectomy and medications. In six countries, the cost of AVS and adrenalectomy combined is >30% of its annual gross domestic product per capita. While most patients had access to spironolactone, it was not universally affordable.
CONCLUSION: Large populations currently do not have access to the healthcare resources required for the optimal management of PA. Greater efforts are required to improve healthcare access and affordability. Future guideline revisions for PA may need to consider these limitations.
OBJECTIVE: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover.
DESIGN: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7).
INTERVENTIONS: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3).
MAIN OUTCOME MEASURES: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured.
RESULTS: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers.
CONCLUSION: LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.