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Primary hyperparathyroidism influences the expression of inflammatory and metabolic genes in adipose tissue.

Christensen MH, Dankel SN, Nordbø Y, Varhaug JE, Almås B, Lien EA, Mellgren G - PLoS ONE (2011)

Bottom Line: We found 608 differentially expressed genes (q-value<0.05), of which 347 were up-regulated and 261 were down-regulated.Analysis of transcription factor binding sites present in the differentially expressed genes corroborated the up-regulation of inflammatory processes.Our findings demonstrate that PHPT strongly influences gene regulation in fat tissue, which may result in altered adipose tissue function and release of pathogenic factors that increase the risk of CVD.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medicine, University of Bergen, Bergen, Norway.

ABSTRACT

Background: Primary hyperparathyroidism (PHPT) is characterised by increased production of parathyroid hormone (PTH) resulting in elevated serum calcium levels. The influence on bone metabolism with altered bone resorption is the most studied clinical condition in PHPT. In addition to this, patients with PHPT are at increased risk of non-skeletal diseases, such as impaired insulin sensitivity, arterial hypertension and increased risk of death by cardiovascular diseases (CVD), possibly mediated by a chronic low-grade inflammation. The aim of this study was to investigate whether adipose tissue reflects the low-grade inflammation observed in PHPT patients.

Methodology/principal findings: Subcutaneous fat tissue from the neck was sampled from 16 non-obese patients with PHPT and from 16 patients operated for benign thyroid diseases, serving as weight-matched controls. RNA was extracted and global gene expression was analysed with Illumina BeadArray Technology. We found 608 differentially expressed genes (q-value<0.05), of which 347 were up-regulated and 261 were down-regulated. Gene ontology analysis showed that PHPT patients expressed increased levels of genes involved in immunity and defense (e.g. matrix metallopeptidase 9, S100 calcium binding protein A8 and A9, CD14, folate receptor 2), and reduced levels of genes involved in metabolic processes. Analysis of transcription factor binding sites present in the differentially expressed genes corroborated the up-regulation of inflammatory processes.

Conclusions/significance: Our findings demonstrate that PHPT strongly influences gene regulation in fat tissue, which may result in altered adipose tissue function and release of pathogenic factors that increase the risk of CVD.

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Related in: MedlinePlus

Functional categorization of differentially expressed genes (Biological Process and Molecular Function).Gene expression in subcutaneous adipose tissue in patients with primary hyperparathyroidism was compared to a control group. Over-represented Biological Processes categories and Molecular Function categories among the differentially expressed genes (q-value<0.05) were found using PANTHER. Bonferroni correction for multiple testing was done and a p-value<0.01 was used as inclusion criterion for categories. The colour intensity displays the statistical significance (−log p-value) of over- and under-represented PANTHER functional categories. Numbers in the table presents the percentage of genes mapping to a given category, e.g. 23% of the 347 up-regulated genes belonged to the Biological Process category Immunity and defense. The overall distribution of a term among all human NCBI genes (25,431) are stated in the first column, e.g. 5% of the genes are expected to map to the Biological Process category Immunity and defense, hence this category is significantly over-represented among the up-regulated genes in patients with PHPT compared to controls. Ref, Reference (based on all human NCBI genes); PHPT patients with primary hyperparathyroidism; Ctr, patients operated for benign thyroid disease without known parathyroid or inflammatory disease; Arrow up, up-regulated/higher expressed genes in patients with PHTP compared to controls; Arrow down, down-regulated/less expressed genes in patients with PHPT compared to controls.
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pone-0020481-g002: Functional categorization of differentially expressed genes (Biological Process and Molecular Function).Gene expression in subcutaneous adipose tissue in patients with primary hyperparathyroidism was compared to a control group. Over-represented Biological Processes categories and Molecular Function categories among the differentially expressed genes (q-value<0.05) were found using PANTHER. Bonferroni correction for multiple testing was done and a p-value<0.01 was used as inclusion criterion for categories. The colour intensity displays the statistical significance (−log p-value) of over- and under-represented PANTHER functional categories. Numbers in the table presents the percentage of genes mapping to a given category, e.g. 23% of the 347 up-regulated genes belonged to the Biological Process category Immunity and defense. The overall distribution of a term among all human NCBI genes (25,431) are stated in the first column, e.g. 5% of the genes are expected to map to the Biological Process category Immunity and defense, hence this category is significantly over-represented among the up-regulated genes in patients with PHPT compared to controls. Ref, Reference (based on all human NCBI genes); PHPT patients with primary hyperparathyroidism; Ctr, patients operated for benign thyroid disease without known parathyroid or inflammatory disease; Arrow up, up-regulated/higher expressed genes in patients with PHTP compared to controls; Arrow down, down-regulated/less expressed genes in patients with PHPT compared to controls.

Mentions: To gain further insight into the potential functions of the differentially expressed genes, we analysed their ontology based on PANTHER functional categories (Fig. 2). Analysis of the up-regulated genes showed that the Biological Process categories Immunity and defense (e.g. S100 calcium binding protein A9 (S100A9, Entrez gene 6280), S100 calcium binding protein A8 (S100A8, Entrez gene 6279), CD14 molecule (CD14, Entrez gene 929)) and Signal transduction (e.g. integrin, beta2/CD18 (ITGB2, Entrez gene 3689), macrophage receptor with collagenous structure (MARCO, Entrez gene 8685)) were strongly over-represented in the PHPT patients compared to controls. Analysing the down-regulated genes in PHPT patients we found an over-representation of the Biological Process categories Lipid, fatty acid and steroid metabolism (e.g. fatty acid synthase (FASN, Entrez gene 2194), stearoyl-CoA desaturase (SCD, Entrez gene 6319)), Coenzyme and prosthetic group metabolism (e.g. acetyl-CoA carboxylase alpha (ACACA, Entrez gene 31), enoyl Ca-A hydratase domain containing 1 (ECHDC1, Entrez gene 55862)), and Carbohydrate metabolism (e.g. aldolase C, fructose-bisphosphate (ALDOC, Entrez gene 230), citrate synthase (CS, Entrez gene 1431)). Over-represented Molecular Function categories for the up-regulated genes included Defense/immunity protein (Complement component (e.g. CD55 molecule (CD55, Entrez gene 1604), complement factor B (CFB, Entrez gene 629)), Immunoglobulin receptor family member (e.g. leukocyte immunoglobuline-like receptor, subfamily B, member 5 (LILRB5, Entrez gene 10990), TYRO protein tyrosine kinase binding protein (TYROBP, Entrez gene 7305)), Extracellular Matrix (e.g. matrix metallopeptidase 9 (MMP9, Entrez gene 4318), collagen, type VIII, alpha 2 (COL8A2, Entrez gene 1296)), and Receptors (e.g. CD14, folate receptor 2 (FOLR2, Entrez gene 2350), colony stimulating factor 1 receptor (CSF1R, Entrez gene 1436)). For the down-regulated genes there was an over-representation of the Molecular Function groups Lyase (e.g. carbonic anhydrase (CA4, Entrez gene 762), malic enzyme 1 (ME1, Entrez gene 4199)) and Oxidoreductase (e.g. SCD, Entrez gene 6319, FASN, Entrez gene 2194).


Primary hyperparathyroidism influences the expression of inflammatory and metabolic genes in adipose tissue.

Christensen MH, Dankel SN, Nordbø Y, Varhaug JE, Almås B, Lien EA, Mellgren G - PLoS ONE (2011)

Functional categorization of differentially expressed genes (Biological Process and Molecular Function).Gene expression in subcutaneous adipose tissue in patients with primary hyperparathyroidism was compared to a control group. Over-represented Biological Processes categories and Molecular Function categories among the differentially expressed genes (q-value<0.05) were found using PANTHER. Bonferroni correction for multiple testing was done and a p-value<0.01 was used as inclusion criterion for categories. The colour intensity displays the statistical significance (−log p-value) of over- and under-represented PANTHER functional categories. Numbers in the table presents the percentage of genes mapping to a given category, e.g. 23% of the 347 up-regulated genes belonged to the Biological Process category Immunity and defense. The overall distribution of a term among all human NCBI genes (25,431) are stated in the first column, e.g. 5% of the genes are expected to map to the Biological Process category Immunity and defense, hence this category is significantly over-represented among the up-regulated genes in patients with PHPT compared to controls. Ref, Reference (based on all human NCBI genes); PHPT patients with primary hyperparathyroidism; Ctr, patients operated for benign thyroid disease without known parathyroid or inflammatory disease; Arrow up, up-regulated/higher expressed genes in patients with PHTP compared to controls; Arrow down, down-regulated/less expressed genes in patients with PHPT compared to controls.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3117792&req=5

pone-0020481-g002: Functional categorization of differentially expressed genes (Biological Process and Molecular Function).Gene expression in subcutaneous adipose tissue in patients with primary hyperparathyroidism was compared to a control group. Over-represented Biological Processes categories and Molecular Function categories among the differentially expressed genes (q-value<0.05) were found using PANTHER. Bonferroni correction for multiple testing was done and a p-value<0.01 was used as inclusion criterion for categories. The colour intensity displays the statistical significance (−log p-value) of over- and under-represented PANTHER functional categories. Numbers in the table presents the percentage of genes mapping to a given category, e.g. 23% of the 347 up-regulated genes belonged to the Biological Process category Immunity and defense. The overall distribution of a term among all human NCBI genes (25,431) are stated in the first column, e.g. 5% of the genes are expected to map to the Biological Process category Immunity and defense, hence this category is significantly over-represented among the up-regulated genes in patients with PHPT compared to controls. Ref, Reference (based on all human NCBI genes); PHPT patients with primary hyperparathyroidism; Ctr, patients operated for benign thyroid disease without known parathyroid or inflammatory disease; Arrow up, up-regulated/higher expressed genes in patients with PHTP compared to controls; Arrow down, down-regulated/less expressed genes in patients with PHPT compared to controls.
Mentions: To gain further insight into the potential functions of the differentially expressed genes, we analysed their ontology based on PANTHER functional categories (Fig. 2). Analysis of the up-regulated genes showed that the Biological Process categories Immunity and defense (e.g. S100 calcium binding protein A9 (S100A9, Entrez gene 6280), S100 calcium binding protein A8 (S100A8, Entrez gene 6279), CD14 molecule (CD14, Entrez gene 929)) and Signal transduction (e.g. integrin, beta2/CD18 (ITGB2, Entrez gene 3689), macrophage receptor with collagenous structure (MARCO, Entrez gene 8685)) were strongly over-represented in the PHPT patients compared to controls. Analysing the down-regulated genes in PHPT patients we found an over-representation of the Biological Process categories Lipid, fatty acid and steroid metabolism (e.g. fatty acid synthase (FASN, Entrez gene 2194), stearoyl-CoA desaturase (SCD, Entrez gene 6319)), Coenzyme and prosthetic group metabolism (e.g. acetyl-CoA carboxylase alpha (ACACA, Entrez gene 31), enoyl Ca-A hydratase domain containing 1 (ECHDC1, Entrez gene 55862)), and Carbohydrate metabolism (e.g. aldolase C, fructose-bisphosphate (ALDOC, Entrez gene 230), citrate synthase (CS, Entrez gene 1431)). Over-represented Molecular Function categories for the up-regulated genes included Defense/immunity protein (Complement component (e.g. CD55 molecule (CD55, Entrez gene 1604), complement factor B (CFB, Entrez gene 629)), Immunoglobulin receptor family member (e.g. leukocyte immunoglobuline-like receptor, subfamily B, member 5 (LILRB5, Entrez gene 10990), TYRO protein tyrosine kinase binding protein (TYROBP, Entrez gene 7305)), Extracellular Matrix (e.g. matrix metallopeptidase 9 (MMP9, Entrez gene 4318), collagen, type VIII, alpha 2 (COL8A2, Entrez gene 1296)), and Receptors (e.g. CD14, folate receptor 2 (FOLR2, Entrez gene 2350), colony stimulating factor 1 receptor (CSF1R, Entrez gene 1436)). For the down-regulated genes there was an over-representation of the Molecular Function groups Lyase (e.g. carbonic anhydrase (CA4, Entrez gene 762), malic enzyme 1 (ME1, Entrez gene 4199)) and Oxidoreductase (e.g. SCD, Entrez gene 6319, FASN, Entrez gene 2194).

Bottom Line: We found 608 differentially expressed genes (q-value<0.05), of which 347 were up-regulated and 261 were down-regulated.Analysis of transcription factor binding sites present in the differentially expressed genes corroborated the up-regulation of inflammatory processes.Our findings demonstrate that PHPT strongly influences gene regulation in fat tissue, which may result in altered adipose tissue function and release of pathogenic factors that increase the risk of CVD.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medicine, University of Bergen, Bergen, Norway.

ABSTRACT

Background: Primary hyperparathyroidism (PHPT) is characterised by increased production of parathyroid hormone (PTH) resulting in elevated serum calcium levels. The influence on bone metabolism with altered bone resorption is the most studied clinical condition in PHPT. In addition to this, patients with PHPT are at increased risk of non-skeletal diseases, such as impaired insulin sensitivity, arterial hypertension and increased risk of death by cardiovascular diseases (CVD), possibly mediated by a chronic low-grade inflammation. The aim of this study was to investigate whether adipose tissue reflects the low-grade inflammation observed in PHPT patients.

Methodology/principal findings: Subcutaneous fat tissue from the neck was sampled from 16 non-obese patients with PHPT and from 16 patients operated for benign thyroid diseases, serving as weight-matched controls. RNA was extracted and global gene expression was analysed with Illumina BeadArray Technology. We found 608 differentially expressed genes (q-value<0.05), of which 347 were up-regulated and 261 were down-regulated. Gene ontology analysis showed that PHPT patients expressed increased levels of genes involved in immunity and defense (e.g. matrix metallopeptidase 9, S100 calcium binding protein A8 and A9, CD14, folate receptor 2), and reduced levels of genes involved in metabolic processes. Analysis of transcription factor binding sites present in the differentially expressed genes corroborated the up-regulation of inflammatory processes.

Conclusions/significance: Our findings demonstrate that PHPT strongly influences gene regulation in fat tissue, which may result in altered adipose tissue function and release of pathogenic factors that increase the risk of CVD.

Show MeSH
Related in: MedlinePlus