Circulating miRNAs and Machine Learning for Lateralizing Primary Aldosteronism
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE264578 | GEO | 2024/10/31
REPOSITORIES: GEO
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Project description:Introduction: Primary aldosteronism (PA) is a major cause of secondary hypertension. The two principal forms of PA are bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) whose differentiation is clinically pivotal, due to their different treatments. Adrenal venous sampling (AVS) is considered to be the gold standard for the differentiation of the two clinical entities, but it is invasive, requires great expertise and is unavailable in many centers. There would be a major clinical need for a reliable and easily accessible diagnostic biomarker. Circulating microRNA were shown to be useful as minimally invasive diagnostic markers in many diseases, but their potential applicability in PA has not yet been investigated. Aims: To determine and compare the circulating microRNA expression profiles of AVS-confirmed APA and BAH plasma samples, and to evaluate their applicability as minimally invasive markers. Methods: 81 AVS-confirmed plasma samples were included. Next-generation sequencing (NGS) was performed on 30 EDTA-anticoagulated plasma samples. Significantly differently expressed miRNAs were validated by real-time RT-qPCR on all samples. Results: We have found relative overexpression of miR-30e-5p, miR-30d-5p, miR-223-3p and miR-7-5p in BAH compared to APA by NGS. Validation of 81 samples confirmed significant overexpression (p=0.03) of miR-7-5p. Regarding the microRNA expressional variations, APA is more heterogenous at the miRNA level compared to BAH. Conclusion: miR-7-5p was significantly overexpressed in BAH samples compared to APA samples, but its sensitivity and specificity values are not good enough for introduction to the clinical practice yet.
2019-02-12 | GSE126386 | GEO
Project description:Primary aldosteronism (PA), the most common form of endocrine hypertension, is characterized by inappropriately elevated aldosterone production via renin-independent mechanisms. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2)-guided sequencing approach. Herein, using CYP11B2-guided whole-exome sequencing (WES) and targeted amplicon sequencing, we detected two closely-stationed somatic variants in SLC30A1 in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2) that were devoid of any of the known aldosterone-driver mutations. SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). PA cases with SLC30A1 mutations showed male dominance and demonstrated increased serum aldosterone concentration compared with age-matched male controls. We tested functional effects of the variant SLC30A1L51_A57del in a doxycycline-inducible system using the human adrenocortical HAC15 cell line. Functional in vitro studies following doxycycline treatment indicated increased adrenal cell aldosterone production, CYP11B2 mRNA expression, CYP11B2 promoter activity, depolarization of the resting membrane potential and increased cytosolic Ca2+ levels in the SLC30A1L51_A57del cells. Collectively, these data support a pathological role for mutant SLC30A1 on the development of PA.
2023-07-03 | GSE236437 | GEO
Project description:Primary and secondary hypertension are major risk factors for cardiovascular disease. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we identify an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah1a-/- mice exhibit altered adrenal gland morphology, as reflected by dysregulated zonation of the glomerulosa, increased aldosterone levels and aldosterone target gene expression, and reduced plasma potassium levels. Genes involved in catecholamine biosynthesis and cAMP signaling are upregulated in the adrenal glands of Siah1a-/- mice, while genes related to retinoic acid signaling and cholesterol biosynthesis are downregulated. Loss of Siah1 leads to increased expression of PIAS1, an E3 SUMO-protein ligase implicated in the suppression of LXR. Notably, SIAH1 sequence variants which impaired SIAH1 ubiquitin ligase activity, resulting in elevated PIAS1 expression, were identified in patients with PA. The involvement of Siah1–PIAS1 in adrenal gland organization and function points to a possible new therapeutic target for hyperaldosteronism.
2018-05-01 | GSE102963 | GEO
Project description:Primary aldosteronism (PA), a common cause of severe hypertension, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) and 80 additional probands with unsolved early-onset PA. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of the identical p.Arg172Gln mutation; all relatives with early-onset PA carried the CLCN2 variant found in probands. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. In this data set, we examined RNA expression in H295R cells transfected with empty vector, WT and p.Arg172Gln CLCN2. Expression of CLCN2 led to increased expression of CYP11B2 and its upstream regulator NR4A2.
2017-12-08 | GSE107030 | GEO
Project description:Primary aldosteronism (PA) is the most common endocrine hypertension comprising 10% of hypertensive patients. A recent series of transcriptome analyses using DNA microarray has shown that neumerous genes are differentially expressed between aldosterone-producing adenoma (APA) and its adjacent adrenal gland (AAG) tissue from the same patient. However, the molecular mechanism(s) of pathogenesis of APA has not yet been fully clarified. Although growing body of evidence has shown that epigenetic abnormalities including DNA methylation play a key role in tumorigenesis, there are few studies with regard to DNA methylation in APA. In the present study, to elucidate the pathogenic relationship between gene expression and DNA methylation in PA, we conducted an integrated analysis of transcriptome and methylome data for paired APA-AAG samples from the same patient. Adrenal specimens were obtained from 7 Japanese patients with APA, who underwent adrenalectomy at Tokyo Medical and Dental University. RNA and DNA samples were extracted from those 7 paired APA and AAG tissues. Gene expression and genome-wide DNA methylation profiles were obtained using SurePrint G3 Human GE 8x60K Microarray (Agilent) and Infinium HumanMethylation450 Beadchip (Illumina), respectively. Transcriptome anlaysis identified 244 significantly (2 fold<) upregulated genes in APA compared to AAG. The upregulated genes include the previously studied genes such as PCP4, ALDH1A2, and CYP11B2, and other genes that have not been previously studied, such as HOXA9, HOXA11, and HOXB9. Gene ontology (GO) analysis for these upregulated genes identified the calcium signaling pathway to be most significantly enriched with the upregulated genes (8 genes). Methylome analysis revealed that APA was globally hypomethylated compared to AAG regardless of gene feature groups, namely, TSS1500, TSS200, 5’UTR, 1stExon, gene body, and 3’UTR. GO analysis for the genes showing hypomethylation at TSS1500/TSS200 regions in APA identified the term “cytokine-cytokine receptor interaction” to be most significantly enriched with hypomethylated genes (37 genes). Integrated analysis of gene expression and genome-wide DNA methylation profiles identified 18 genes that are upregulated and whose TSS1500/TSS200 regions are hypomethylated in APA compared to AAG. These genes include CYP11B2 and MC2R (ACTH receptor). In conclusion, this is the first genome-wide study for PA that integrated transcriptome and methylome data. Global DNA hypomethylation in APA and concordant transcriptional up-regulation of some key genes, such as CYP11B2 and MC2R, may play crucial roles in the pathophysiological significance in PA. Adrenal specimens were obtained from 7 Japanese patients with APA, who underwent adrenalectomy at Tokyo Medical and Dental University. RNA and DNA samples were extracted from those 7 paired APA and AAG tissues. Gene expression and genome-wide DNA methylation profiles were obtained using SurePrint G3 Human GE 8x60K Microarray (Agilent) and Infinium HumanMethylation450 Beadchip (Illumina), respectively.
2015-05-09 | E-GEOD-60043 | biostudies-arrayexpress
Project description:Primary aldosteronism (PA) is the most common endocrine hypertension comprising 10% of hypertensive patients. A recent series of transcriptome analyses using DNA microarray has shown that neumerous genes are differentially expressed between aldosterone-producing adenoma (APA) and its adjacent adrenal gland (AAG) tissue from the same patient. However, the molecular mechanism(s) of pathogenesis of APA has not yet been fully clarified. Although growing body of evidence has shown that epigenetic abnormalities including DNA methylation play a key role in tumorigenesis, there are few studies with regard to DNA methylation in APA. In the present study, to elucidate the pathogenic relationship between gene expression and DNA methylation in PA, we conducted an integrated analysis of transcriptome and methylome data for paired APA-AAG samples from the same patient. Adrenal specimens were obtained from 7 Japanese patients with APA, who underwent adrenalectomy at Tokyo Medical and Dental University. RNA and DNA samples were extracted from those 7 paired APA and AAG tissues. Gene expression and genome-wide DNA methylation profiles were obtained using SurePrint G3 Human GE 8x60K Microarray (Agilent) and Infinium HumanMethylation450 Beadchip (Illumina), respectively. Transcriptome anlaysis identified 244 significantly (2 fold<) upregulated genes in APA compared to AAG. The upregulated genes include the previously studied genes such as PCP4, ALDH1A2, and CYP11B2, and other genes that have not been previously studied, such as HOXA9, HOXA11, and HOXB9. Gene ontology (GO) analysis for these upregulated genes identified the calcium signaling pathway to be most significantly enriched with the upregulated genes (8 genes). Methylome analysis revealed that APA was globally hypomethylated compared to AAG regardless of gene feature groups, namely, TSS1500, TSS200, 5’UTR, 1stExon, gene body, and 3’UTR. GO analysis for the genes showing hypomethylation at TSS1500/TSS200 regions in APA identified the term “cytokine-cytokine receptor interaction” to be most significantly enriched with hypomethylated genes (37 genes). Integrated analysis of gene expression and genome-wide DNA methylation profiles identified 18 genes that are upregulated and whose TSS1500/TSS200 regions are hypomethylated in APA compared to AAG. These genes include CYP11B2 and MC2R (ACTH receptor). In conclusion, this is the first genome-wide study for PA that integrated transcriptome and methylome data. Global DNA hypomethylation in APA and concordant transcriptional up-regulation of some key genes, such as CYP11B2 and MC2R, may play crucial roles in the pathophysiological significance in PA. Adrenal specimens were obtained from 7 Japanese patients with APA, who underwent adrenalectomy at Tokyo Medical and Dental University. RNA and DNA samples were extracted from those 7 paired APA and AAG tissues. Gene expression and genome-wide DNA methylation profiles were obtained using SurePrint G3 Human GE 8x60K Microarray (Agilent) and Infinium HumanMethylation450 Beadchip (Illumina), respectively.
2015-05-09 | E-GEOD-60042 | biostudies-arrayexpress
Project description:Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. Inactivation of Rarα in mice led to major structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA.
2019-10-21 | GSE136801 | GEO
Project description:Primary aldosteronism is frequently caused by an adrenocortical aldosterone-producing adenoma (APA) carrying a somatic mutation that drives aldosterone overproduction. APAs with a mutation in KCNJ5 (APA-KCNJ5MUT) are characterized by heterogeneous CYP11B2 (aldosterone synthase) expression, a particular cellular composition and larger tumor diameter than those with wild-type KCNJ5 (APA-KCNJ5WT). Here, we used spatial transcriptomics profiling of adrenal tissue cryosections to define the role of transcriptomic reprogramming in APA pathophysiology. Our findings advance the understanding of the transcriptional context of inter- and intra-tumoral APA heterogeneity and provide novel insight into the genotype-dependent tumor expansion capabilities of APAs.
2024-08-13 | GSE274314 | GEO
Project description:Primary aldosteronism (PA) is the most common endocrine hypertension comprising 10% of hypertensive patients. A recent series of transcriptome analyses using DNA microarray has shown that neumerous genes are differentially expressed between aldosterone-producing adenoma (APA) and its adjacent adrenal gland (AAG) tissue from the same patient. However, the molecular mechanism(s) of pathogenesis of APA has not yet been fully clarified. Although growing body of evidence has shown that epigenetic abnormalities including DNA methylation play a key role in tumorigenesis, there are few studies with regard to DNA methylation in APA. In the present study, to elucidate the pathogenic relationship between gene expression and DNA methylation in PA, we conducted an integrated analysis of transcriptome and methylome data for paired APA-AAG samples from the same patient. Adrenal specimens were obtained from 7 Japanese patients with APA, who underwent adrenalectomy at Tokyo Medical and Dental University. RNA and DNA samples were extracted from those 7 paired APA and AAG tissues. Gene expression and genome-wide DNA methylation profiles were obtained using SurePrint G3 Human GE 8x60K Microarray (Agilent) and Infinium HumanMethylation450 Beadchip (Illumina), respectively. Transcriptome anlaysis identified 244 significantly (2 fold<) upregulated genes in APA compared to AAG. The upregulated genes include the previously studied genes such as PCP4, ALDH1A2, and CYP11B2, and other genes that have not been previously studied, such as HOXA9, HOXA11, and HOXB9. Gene ontology (GO) analysis for these upregulated genes identified the calcium signaling pathway to be most significantly enriched with the upregulated genes (8 genes). Methylome analysis revealed that APA was globally hypomethylated compared to AAG regardless of gene feature groups, namely, TSS1500, TSS200, 5’UTR, 1stExon, gene body, and 3’UTR. GO analysis for the genes showing hypomethylation at TSS1500/TSS200 regions in APA identified the term “cytokine-cytokine receptor interaction” to be most significantly enriched with hypomethylated genes (37 genes). Integrated analysis of gene expression and genome-wide DNA methylation profiles identified 18 genes that are upregulated and whose TSS1500/TSS200 regions are hypomethylated in APA compared to AAG. These genes include CYP11B2 and MC2R (ACTH receptor). In conclusion, this is the first genome-wide study for PA that integrated transcriptome and methylome data. Global DNA hypomethylation in APA and concordant transcriptional up-regulation of some key genes, such as CYP11B2 and MC2R, may play crucial roles in the pathophysiological significance in PA.
2015-05-09 | GSE60043 | GEO
Project description:Primary aldosteronism (PA) is the most common endocrine hypertension comprising 10% of hypertensive patients. A recent series of transcriptome analyses using DNA microarray has shown that neumerous genes are differentially expressed between aldosterone-producing adenoma (APA) and its adjacent adrenal gland (AAG) tissue from the same patient. However, the molecular mechanism(s) of pathogenesis of APA has not yet been fully clarified. Although growing body of evidence has shown that epigenetic abnormalities including DNA methylation play a key role in tumorigenesis, there are few studies with regard to DNA methylation in APA. In the present study, to elucidate the pathogenic relationship between gene expression and DNA methylation in PA, we conducted an integrated analysis of transcriptome and methylome data for paired APA-AAG samples from the same patient. Adrenal specimens were obtained from 7 Japanese patients with APA, who underwent adrenalectomy at Tokyo Medical and Dental University. RNA and DNA samples were extracted from those 7 paired APA and AAG tissues. Gene expression and genome-wide DNA methylation profiles were obtained using SurePrint G3 Human GE 8x60K Microarray (Agilent) and Infinium HumanMethylation450 Beadchip (Illumina), respectively. Transcriptome anlaysis identified 244 significantly (2 fold<) upregulated genes in APA compared to AAG. The upregulated genes include the previously studied genes such as PCP4, ALDH1A2, and CYP11B2, and other genes that have not been previously studied, such as HOXA9, HOXA11, and HOXB9. Gene ontology (GO) analysis for these upregulated genes identified the calcium signaling pathway to be most significantly enriched with the upregulated genes (8 genes). Methylome analysis revealed that APA was globally hypomethylated compared to AAG regardless of gene feature groups, namely, TSS1500, TSS200, 5’UTR, 1stExon, gene body, and 3’UTR. GO analysis for the genes showing hypomethylation at TSS1500/TSS200 regions in APA identified the term “cytokine-cytokine receptor interaction” to be most significantly enriched with hypomethylated genes (37 genes). Integrated analysis of gene expression and genome-wide DNA methylation profiles identified 18 genes that are upregulated and whose TSS1500/TSS200 regions are hypomethylated in APA compared to AAG. These genes include CYP11B2 and MC2R (ACTH receptor). In conclusion, this is the first genome-wide study for PA that integrated transcriptome and methylome data. Global DNA hypomethylation in APA and concordant transcriptional up-regulation of some key genes, such as CYP11B2 and MC2R, may play crucial roles in the pathophysiological significance in PA.
2015-05-09 | GSE60042 | GEO