LTBP1 protein identified as potential biomarker, therapy target in PAH
Protein plays a role in the TGF-beta pathway
The protein LTBP1 is active at high levels in pulmonary arterial hypertension (PAH) and may be a diagnostic marker and therapeutic target in the disease, a new study indicates.
“Our study suggests that LTBP1 is involved in the development of PAH and serves as a potential diagnostic and therapeutic target for PAH,” the researchers wrote in “Bioinformatics analysis of the immune cell infiltration characteristics and correlation with crucial diagnostic markers in pulmonary arterial hypertension,” which was published in BMC Pulmonary Medicine.
Inflammation is thought to play a critical role in driving lung and blood vessel damage in PAH, but the molecular details that cause it are not fully understood, leading scientists in China to identify inflammatory markers that could help detect PAH or serve as targets for treating it.
They obtained data from multiple datasets of human lung samples from people with or without PAH, then tested for differentially expressed genes, those significantly more or less active with PAH compared to without it.
Higher, lower levels of certain cells in PAH
The analysis identified 223 genes that were overactive in PAH and another 196 genes that were less active. Many of these genes are involved in molecular pathways that play a role in PAH, such as the TGF-beta pathway.
The differences in gene activity regarding the types of immune cells involved suggested that people with PAH had higher levels of certain immune cell types, including several subsets of T-cells and resting mast cells (a type of immune cell that’s prominent in allergic reactions). They also had lower levels of other immune cell types, including activated mast cells, monocytes, and neutrophils.
The scientists analyzed the differentially expressed genes based on their functionality, looking for so-called “hub genes” that interact with many of the other dysregulated genes. They identified four hub genes — LTBP1, which was expressed at high levels with PAH, and CR1, TXNRD1 and TLR1 — all expressed at low levels in PAH.
To test how well these hub genes could identify PAH, the researchers calculated a statistical metric called the area under the receiver operating characteristic curve (AUC). This tests how well a given parameter can differentiate between two groups (i.e., PAH or not). AUC values range from 0.5 to 1, with higher numbers indicating a better ability to differentiate.
For all four hub genes, the AUC was higher than 0.9 in the datasets analyzed. The highest AUC of 0.968 was seen for LTBP1, the one expressed at higher levels in PAH. This gene provides instructions for making a protein, also called LTBP1, which has a role in the TGF-beta pathway.
The researchers showed LTBP1 gene activity correlated with levels of some immune cells in the human datasets. Further experiments in a rat model of PAH showed the LTBP1 protein was active at heightened levels in the lungs and pulmonary arteries.
“LTBP1 is upregulated and correlated to immune [cell] infiltration in PAH, identified as a new critical biomarker for PAH,” the researchers said, adding more research was needed to examine the role of this protein in PAH.
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