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

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.

Figure 1. Correspondence analysis showing projection of samples.

Patients with primary hyperparathyroidism are shown with red dots and the control group are shown with blue squares. The first principal component shows the largest variance in the dataset with 8.83% and the second principal component represents the second largest variance with 6.69%. Patients with primary hyperparathyroidism are separated from the control group along both axes.

Figure 2. 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.