Researchers Find 4 Biomarkers Linked to Copper Metabolism in PAH

Researchers have identified 4 biomarkers related to copper metabolism in patients with pulmonary arterial hypertension (PAH): DDIT3, NFKBIA, OSM, and PTGER4.

These biomarkers were found to have considerable diagnostic values based on bioinformatics analyses, and a gene-drug network was further constructed.

These findings were published in BMC Pulmonary Medicine. The study authors said these results may have significant implications for developing new diagnostic biomarkers and actionable targets to expand PAH treatment options.

To come to these findings, the authors downloaded PAH-related datasets from the Gene Expression Omnibus database, and obtained 2067 copper metabolism-related genes (CMGs) from the GeneCards database. One dataset had 71 samples with 30 used as a control group, and another had 17 samples with 6 used as a control group.

They then used differential expression analysis and the Venn algorithm to acquire differentially expressed CMGs (DE-CMGs), which were then used for the coexpression network construction to screen candidate PAH-associated key genes.

Receiver operating characteristic (ROC) analysis was then conducted to verify the predictive performance of the model, and genes with area under the curve (AUC) values greater than 0.8 were selected as diagnostic genes. Researchers then detected the biomarkers, analyzed their function, and predicted potential therapeutic drugs for PAH using these biomarkers. Biomarker expression in clinical samples was verified by real-time quantitative polymerase chain reaction.

ROC analysis showed the biomarkers DDIT3, NFKBIA, OSM, and PTGER4 performed well with AUCs greater than 0.7, and the high expression groups for the biomarkers were enriched in protein activity-related pathways, including protein export, spliceosome, and proteasome.

Regarding immune cell types, the authors also found memory B cells, monocytes, M0 macrophages, M2 macrophages, and neutrophils were increased in PAH. On the other hand, resting CD4 memory T cells, naïve B cells, and follicular helper T cells were decreased in PAH.

“Immune cells play an indispensable role in the process of pulmonary hypertension vessel remodeling,” the authors wrote. “Therefore, attention should be given to the mechanism of immune cell infiltration in patients with PAH.”

They also noted that current PAH treatments generally target vasoconstriction by 3 different modalities: nitric oxide to soluble guanylate cyclase to cGMP levels, the endothelin pathway, and the prostacyclin pathway. Additionally, combination therapy has become more of the gold standard of care in patients with PAH and is more widely used in clinical practice.

The results also give clinicians a reference to decide which drugs should be used in combination with current targeted drugs to improve prognosis for patients with PAH, as well as which drugs should be used with caution to prevent clinical deterioration of PAH. Gene-drug network in the study showed streptozocin, ibuprofen, and celecoxib were shared by biomarkers DDIT3 and PTGER4

“Among them, ibuprofen and celecoxib are non-steroidal anti-inflammatory drugs (NSAIDs) that are commonly used in the clinic, and it has been reported that NSAIDs consumption during pregnancy contributes to an increased risk of persistent pulmonary hypertension of the newborns,” the authors added. “Physicians should be alert to the potential dangers of these drugs to PAH patients.”

According to the authors, this research revealed an association between copper metabolism-related genes and PAH.

“These biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of PAH patients,” they wrote. “Copper metabolism has potential as a new diagnostic biomarker as well as a targeted therapy for PAH, while the underlying mechanisms need to be clarified further in future studies.”

Reference

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