Two Likely Biomarkers for PAH Diagnosis, Progression Identified
Changes seen in activity of 2 key genes with pulmonary arterial hypertension
Two new biomarkers to assess pulmonary arterial hypertension (PAH) were discovered through large-scale analysis of gene activity profiles using computer software, a study reported.
These biomarkers, the activity of the genes PNISR and HNRNPH1, may help diagnose PAH, monitor its progression, or measure responses to therapy. They also may highlight underlying disease processes, helping to guide the development of targeted treatments that modify the disease to slow or halt its progression.
Studies with larger groups of PAH patients are needed to validate these findings, and further work is needed to understand the role of these biomarkers in PAH development, the researchers suggested.
The biomarker study, “The identification and verification of hub genes associated with pulmonary arterial hypertension using weighted gene co-expression network analysis,” was published in the journal BMC Pulmonary Medicine.
Changes in gene activity as identified in lung tissues samples
PAH is caused by the narrowing of pulmonary arteries, the blood vessels that transport blood from the heart to the lungs, which restricts blood flow and causes high blood pressure, or hypertension. While there is no cure for PAH to date, several therapies manage disease symptoms by relaxing and widening arteries to improve blood flow and lower blood pressure.
Bioinformatics is a research field that uses computer software tools to analyze and understand biological data, especially large and complex datasets. Recently, bioinformatics has been applied to cell-wide gene expression (gene activity) data to find potential biomarkers in complex diseases.
When compared to healthy tissue, changes in gene expression in affected tissue may highlight genes that participate in disease development and thus act as a biomarker.
Researchers in China applied bioinformatic tools to analyze the Gene Expression Omnibus (GEO) database, a U.S. public data repository containing curated gene expression profiles. They focused on gene expression data from lung tissue samples collected from 32 PAH patients and 25 unaffected people serving as controls.
The team first identified 2,298 differentially expressed genes, meaning genes whose activity in lung tissue differed between PAH and controls. Among them, 1,140 genes were more active, or upregulated, while 1,158 genes were less active, or downregulated. Further refinement to find genes that showed a strong statistical correlation with PAH reduced the number to 597 differentially expressed genes.
Functional enrichment analysis was applied to determine whether some biological functions are enriched among these differentially expressed genes. Results showed that “pathways in cancer” played a significant role in PAH, which was consistent with previous data showing that the abnormal biology seen in pulmonary arteries with severe PAH resembled a cancer-like state, the team noted.
Because each of the differentially expressed genes carried instructions to make proteins, the researchers then conducted an analysis to find those that interacted with each other. In particular, they looked for proteins interacting with many different proteins, forming so-called hubs, which represent proteins fundamental to various biological processes.
Four hub genes were found that encoded proteins participating in multiple interactions: VEGFA, KIT, PNISR, and HNRNPH1. To validate these findings, their expression was measured in human pulmonary artery smooth muscle cells after exposure to cobalt chloride — a substance that artificially induces low oxygen levels (hypoxia) to mimic PAH conditions.
Among the four candidate genes, PNISR and HNRNPH1 were upregulated after cobalt chloride exposure compared to unexposed controls, “which was in line with the bioinformatics analysis,” the researchers noted. Similar results were seen using pulmonary artery smooth muscle cells isolated from rats.
Statistical calculation found that increased PNISR expression could distinguish cobalt chloride-treated cells from control cells with an accuracy of 81.5%. For HNRNPH1, the accuracy was 74.4%.
“PNISR and HNRNPH1 had a powerful ability to discriminate PAH from the controls,” the investigators wrote.
Of note, the PNISR gene encodes a newly identified protein whose function is unclear, but it is rich in serine and arginine amino acids, which are protein building blocks. Such proteins are known to participate in RNA metabolism. The HNRNPH1 encodes a protein known to also interact with RNA.
“PNISR and HNRNPH1 were determined to be potential biomarkers in PAH,” the researchers concluded. “Our results indicate that PNISR and HNRNPH1 participate in the development of PAH and serve as potential diagnosis and therapeutic targets for PAH.”
“Further research [is] required to investigate the role of PNISR and HNRNPH1 on the development of PAH, and the expansion of the sample size is needed to validate the efficacy of PNISR and HNRNPH1 as biomarkers for PAH,” they added.
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