Gene activity analysis of whole blood reveals 3 major PAH subgroups

Gene activity analysis of whole blood collected from people with pulmonary arterial hypertension (PAH) identified three patient subgroups associated with distinct clinical characteristics and outcomes, a study concluded.

These findings can provide molecular insights into the development of PAH, improve disease risk assessments and potentially guide individual treatment strategies, the scientists noted.

The study, “Biological heterogeneity in idiopathic pulmonary arterial hypertension identified by unsupervised transcriptomic profiling of whole bloodwas published in the journal Nature Communication.

In PAH, the pulmonary arteries that carry blood to the lungs narrow, restricting blood flow and increasing blood pressure (hypertension).

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The cause of idiopathic PAH (IPAH) is currently unknown and the diagnosis is usually confirmed after other forms of PAH have been ruled out, such as infections, use of certain medications, or other illnesses. Accordingly, IPAH patients show a wide range of differences in disease progression, treatment responses, and survival.

Several studies have found mutations in genes associated with both IPAH and inherited forms of PAH (HPAH), as well as disease-related signatures in protein production and gene activity that have identified biomarkers to aid diagnosis and prognosis (outcomes).

However, molecular heterogeneity (variability) in cases of IPAH and HPAH has not been reported so far.

Now researchers based at the University of Sheffield in the UK, together with colleagues in the UK and US, have taken whole blood samples from patients with IPAH and HPAH and analyzed global genetic activity using machine learning to study the biological heterogeneity of PAH.

Participants were recruited from the National Cohort Study in Idiopathic and Hereditary Pulmonary Hypertension in the UK (NCT01907295), designed to explore genetic and environmental contributions to the disease. Information was collected every six months as part of routine clinical care.

Gene expression (activity) and identification were determined by RNA sequencing from whole blood samples isolated from 359 patients with IPAH and HPAH, plus 13 patient relatives and 21 healthy controls unrelated. The study included both new (incident) cases and prevalent cases diagnosed at least six months prior to the study.

The analysis identified five distinct subgroups of patients based on different levels of gene expression.

The largest of these groups contained 129 participants (Subgroup I), who had the lowest survival – 53% were alive after a median of five years. The second largest group (subgroup II) of 112 patients demonstrated the best survival (78% survival at a median of five years).

Subgroup V, with 89, demonstrated a mixed gene expression pattern and average survival outcome compared to subgroups I and II. Subgroups III, with 19 patients, and IV, with 10 patients, also had distinct gene expression profiles, but statistical analysis was not possible due to the small size of these groups; thus, the team focused on subgroups I, II and V.

A detailed review of gene expression profiles identified 57 genes with specific associations to each subgroup. the ALAS2 The gene, related to porphyria, appeared in the expression signatures of subgroups I and II, but was approximately twice as high in group I (poor prognosis) than in group II (good prognosis).

Several genes that code for antibody proteins (immunoglobins) were “key markers” for each subgroup, which had either low expression (down-regulated) in subgroup I or high expression (down-regulated upwards) in subgroup II.

In subgroup II, upregulation was high for Noggin, a protein that blocks the action of BMP4, which is associated with the development of PAH, “highlighting its association with good prognosis,” the authors wrote. researchers. In contrast, the antibody and Noggin genes were more than double downregulated in subgroup I, “consistent with contemporary understanding of disrupted BMP and inflammatory signaling in the pathogenesis of PAH.” [disease development]“, they added.

In addition to higher antibody gene expression, immune cell analysis revealed a greater abundance of lymphocytes (B cells and T cells) and memory B cells in subgroup II. In the poor prognosis (subgroup I), there was a lower proportion of lymphocytes and a higher number of neutrophils, which was statistically significant. A higher neutrophil to lymphocyte ratio is a known indicator of poor overall survival.

Additionally, a significantly higher number of patients carried a variant of HLA-DP, an immune cell surface protein that is essential for immune responses and shown to be associated with survival in a large study. IPAH.

An assessment of clinical characteristics in the gene expression subgroups revealed that patients in subgroup I were significantly older (45–70 years) than the other subgroups; had the highest levels of NT-proBNP, a marker of heart damage; and the shortest distance traveled in six minutes (6MWD).

Subgroup I also had the highest proportion of patients (50.4%) within functional class (FC) III, who experience shortness of breath and fatigue during normal activities. In contrast, subgroup II had a higher number of patients with FC I (16.5%) or II (41.3%) with either no symptoms or symptoms on exertion.

Important clinical features that described different gene expression signatures in subgroup I included C-reactive protein (CRP), a sign of inflammation; creatinine, a marker of kidney function; age at diagnosis; 6MWD; and body mass index (BMI), a measure of body fat.

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In subgroup II, clinical features were CRP, creatinine, age at diagnosis, BMI, 6MWD, blood oxygen level (before-6MWD), and right atrial area , associated with PAH outcomes.

Higher CRP was a marker for subgroup I, and lower levels indicated subgroups II and V. Conversely, shorter 6MWD was associated with subgroup I and longer distance with subgroups -groups II and V. Older age at diagnosis and higher BMI, right atrium and creatinine were associated with subgroup I.

Finally, the results were validated using these clinical characteristics associated with gene expression levels to classify 197 patients without whole blood RNA profiling. Again, three groups were categorized similar to subgroups I, II, and V and showed differences in their 10-year survival outcomes.

“These independently validated results provide evidence for the existence of 3 major subgroups (endophenotypes) in the IPAH classification, may improve risk stratification and provide molecular insights into the pathogenesis of IPAH,” wrote the scientists.

“Furthermore, these data promise that these molecular endophenotypes can be adapted to existing therapies, may offer an alternative approach to tailoring and assessing individual response to treatment, in PAH,” they added.


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