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Massive analysis of cDNA Ends (MACE) and miRNA expression profiling identifies proatherogenic pathways in chronic kidney disease.

Zawada AM, Rogacev KS, Müller S, Rotter B, Winter P, Fliser D, Heine GH - Epigenetics (2013)

Bottom Line: Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes.Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD.After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine IV; Saarland University Medical Center; Homburg, Germany.

ABSTRACT
Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.

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Figure 1. Analysis of MACE results. (A) Unsupervised hierarchical cluster analysis with Euclidean distance measure of the 80 differentially expressed genes derived from MACE analysis. (B) Principle component analysis (PCA) of all expressed genes from the 20 examined samples. The first (x-axis) and second principal component (y-axis) accounted for 16% and 9%, respectively, of the total variation in the data. (C) Pearson product-moment correlation coefficient (PCC) for all samples compared within the control and patient group as well as between both groups.
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Figure 1: Figure 1. Analysis of MACE results. (A) Unsupervised hierarchical cluster analysis with Euclidean distance measure of the 80 differentially expressed genes derived from MACE analysis. (B) Principle component analysis (PCA) of all expressed genes from the 20 examined samples. The first (x-axis) and second principal component (y-axis) accounted for 16% and 9%, respectively, of the total variation in the data. (C) Pearson product-moment correlation coefficient (PCC) for all samples compared within the control and patient group as well as between both groups.

Mentions: Statistical data analysis (R) comprised hierarchical clustering of differentially expressed transcripts (Fig. 1A) as well as principal component analysis (Fig. 1B) and Pearson correlations (Fig. 1C) of all transcripts. We found HD patients and control subjects to cluster differentially; moreover, in line with their broad spectrum of comorbidity, HD patients displayed much higher heterogeneity in gene expression than control subjects.


Massive analysis of cDNA Ends (MACE) and miRNA expression profiling identifies proatherogenic pathways in chronic kidney disease.

Zawada AM, Rogacev KS, Müller S, Rotter B, Winter P, Fliser D, Heine GH - Epigenetics (2013)

Figure 1. Analysis of MACE results. (A) Unsupervised hierarchical cluster analysis with Euclidean distance measure of the 80 differentially expressed genes derived from MACE analysis. (B) Principle component analysis (PCA) of all expressed genes from the 20 examined samples. The first (x-axis) and second principal component (y-axis) accounted for 16% and 9%, respectively, of the total variation in the data. (C) Pearson product-moment correlation coefficient (PCC) for all samples compared within the control and patient group as well as between both groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928179&req=5

Figure 1: Figure 1. Analysis of MACE results. (A) Unsupervised hierarchical cluster analysis with Euclidean distance measure of the 80 differentially expressed genes derived from MACE analysis. (B) Principle component analysis (PCA) of all expressed genes from the 20 examined samples. The first (x-axis) and second principal component (y-axis) accounted for 16% and 9%, respectively, of the total variation in the data. (C) Pearson product-moment correlation coefficient (PCC) for all samples compared within the control and patient group as well as between both groups.
Mentions: Statistical data analysis (R) comprised hierarchical clustering of differentially expressed transcripts (Fig. 1A) as well as principal component analysis (Fig. 1B) and Pearson correlations (Fig. 1C) of all transcripts. We found HD patients and control subjects to cluster differentially; moreover, in line with their broad spectrum of comorbidity, HD patients displayed much higher heterogeneity in gene expression than control subjects.

Bottom Line: Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes.Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD.After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine IV; Saarland University Medical Center; Homburg, Germany.

ABSTRACT
Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.

Show MeSH
Related in: MedlinePlus