Gene activity may predict disease severity in IPAH, CTEPH
Correlations show 'prognostic value' warranting further study, researchers say
Researchers have identified distinct genetic changes tied to the severity of idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH).
Data showed that the expression (activity) of the ABCA3 gene was lower in IPAH patients, while that of the SMAD9 gene was increased in CTEPH, particularly among those with the most severe functional impairments. The researchers said the results suggest potential biomarkers.
“The correlations between gene expression and clinical parameters emphasize their prognostic value,” the researchers wrote. “These results represent preliminary findings and need further validation in larger cohorts.”
The study, “Evaluation of gene and microRNA expression patterns in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension as rare diseases,” was published in Respiratory Medicine.
Pulmonary hypertension (PH) is a group of diseases characterized by high blood pressure in the pulmonary arteries, the blood vessels that pass through the lungs. A narrowing of the pulmonary arteries causes high blood pressure in PAH, while in CTEPH, it’s caused by blood clots blocking these blood vessels.
Genes and their regulators
Among the factors implicated in the development of PH are changes in the expression of certain genes and the levels of microRNAs (miRNAs), small RNA molecules that help regulate protein production.
Studying molecular processes that are altered in diseases can help identify biomarkers to support diagnosis, monitor disease progression or treatment response, or inform the development of new therapeutic targets.
However, “there are a limited number of gene expression studies focusing on PH-related genes in IPAH and CTEPH groups,” the researchers wrote.
The team in Turkey sought to examine changes in the expression of PH-related genes and miRNAs in immune cells from the blood of 15 adults with idiopathic PAH (PAH of unknown cause), 12 CTEPH patients, and 12 healthy individuals.
“This study hypothesized that PH-related genes and their … regulators, miRNAs, may show specific expression patterns in IPAH and CTEPH patients,” the team noted.
Of the PH-related genes tested, the expression of the ABCA3 gene was significantly lower in IPAH patients compared with healthy controls, particularly among those with severe disease, as indicated by the New York Heart Association Functional Classification.
ABCA3 encodes a protein critical for producing pulmonary surfactant, a liquid substance that reduces surface tension in the alveoli, the tiny air sacs in the lungs, preventing lung collapse during exhalation. Mutations that lower ABCA3 expression are tied to pediatric lung diseases, including childhood interstitial lung disorder.
The study “supports the downregulation of ABCA3, which could contribute to disease progression or severity to a much milder extent than seen in pediatric respiratory diseases,” the researchers wrote.
In CTEPH patients, the expression of SMAD9 was significantly higher than in controls — again, particularly among those with severe disease.
SMAD9, a gene linked with heritable PAH, is involved in signaling pathways, and defects in this gene can lead to excessive growth of smooth muscle cells that line the pulmonary arteries. The team suggested this may enhance the stability of blood clots that drive CTEPH.
Of the miRNAs examined, regardless of disease severity, miR-30a-5p expression was markedly higher in the IPAH group, and miR-210-3p levels were elevated in both IPAH and CTEPH groups. The expression levels of miR-126-3p were also increased in patients with IPAH and CTEPH.
“Our findings for the IPAH group showed similar trends to previous research on miR-30a-5p, demonstrating that miR-30a-5p levels are elevated in patients with PAH,” the team wrote.
The researchers compared the gene expression results to clinical assessments of disease severity.
The lower expression of several genes in IPAH patients (ATP13A3, BMPR1A, BMPR2, KCNK3, SMAD9, SOX17, and TET2) correlated with higher systolic pulmonary artery pressure (the blood pressure in the pulmonary arteries during a heartbeat).
In CTEPH, higher expression of the NOTCH1 gene was linked with elevated pulmonary artery wedge pressure, a buildup of pressure in the left side of the heart.
A comparison of the genes themselves revealed correlations between the expression of SMAD9 and both BMPR1A and BMPR2, as well as between BMPR1A and BMPR2 across both groups. In IPAH, TET2 showed strong positive correlations with SMAD9 and BMPR2.
When the team compared gene expression to miRNA levels, they found that NOTCH1 expression in both groups correlated with miR-30a-5p levels.
“Downregulation of ABCA3 in patients with IPAH and upregulation of SMAD9 in CTEPH patients may offer initial evidence to guide future investigations,” the researchers concluded. “Our study makes a great contribution as it links expression profiles of IPAH and CTEPH patients with their clinical features.”
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