In patients with pulmonary arterial hypertension (PAH), 4 copper metabolism biomarkers with considerable diagnostic value—DDIT3, NFKBIA, OSM, and PTGER4—have been identified, and a gene-drug network has been constructed, according to findings from an analysis published in the journal BMC Pulmonary Medicine.

The pathogenesis of PAH and its associated biomarkers currently are being evaluated, with the role played by copper metabolism in PAH remaining to be elucidated. The PAH-related GSE33463 and GSE113439 datasets, along with the corresponding sample grouping information, were downloaded from the Gene Expression Omnibus (GEO) database. Additionally, 2067 copper metabolism-related genes (CMGs) were obtained from the GeneCards database.

The researchers utilized differential expression analysis and the Venn algorithm to acquire the differentially expressed CMGs (DE-CMGs), with these DE-CMGs then used in the co-expression network construction to screen candidate key genes associated with PAH. The predictive performance of the model was tested with receiver operating characteristic (ROC) analysis. Genes with area under the curve (AUC) values of more than 0.8 were chosen as diagnostic genes.

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Next, support vector machine, least absolute shrinkage and selection operator regression, and Venn diagrams were used to detect biomarkers. Further, gene set enrichment analysis was conducted to examine the function of biomarkers, and immune-associated investigations were utilized to explore the infiltration of immune cells.

The drug-gene interaction database was applied to predict therapeutic agents for patients with PAH via use of the biomarkers. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify the expression of biomarkers in clinical samples.

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Results of the study showed that the 4 biomarkers screened all performed well, exhibiting AUCs of more than 0.7. The high expression groups for the 4 biomarkers were enriched in protein activity–related pathways, which included protein export, spliceosome, and proteasome.

Additionally, 8 immune cell types differed significantly between the PAH group and the control group, including naïve B cells, memory B cells, and resting memory CD4 T cells. Following this, a gene-drug network was constructed, which revealed that streptozocin, ibuprofen, and celecoxib were shared by the PTGER4 and the DDIT3 biomarkers. Moreover, rt-qPCR results in clinical samples further verified the findings of the public database for the expression of NFKBIA and OSM.

“This study uncovers a link between copper metabolism-related genes and pulmonary hypertension, highlighting several biomarkers,” according to the researchers. “The results of this study may have significant implications for the development of new diagnostic biomarkers and actionable targets to expand treatment options for [patients with] PAH.”


Wang L, Zhang W, Li C, Chen X, Huang J. Identification of biomarkers related to copper metabolism in patients with pulmonary arterial hypertension. BMC Pulm Med. 2023;23(1):31. doi:10.1186/s12890-023-02326-6