Gene Profile May Help Distinguish PAH from ILD in SSc Patients, Study Suggests

Ana Pena, PhD avatar

by Ana Pena, PhD |

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genes and disease risk

Among patients with systemic sclerosis (SSc), those who have pulmonary arterial hypertension (PAH) have a distinct pattern of active and silent genes compared with those who develop interstitial lung disease (ILD), a preliminary study suggests.

As some differences may already be present early in disease, this information may be useful to early identification of either of the two conditions in patients with SSc, researchers say.

The study, “Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease” was published in the Journal of Scleroderma and Related Disorders.

PAH and ILD often coexist with and contribute to morbidity and mortality in SSc patients.

In theory, a person with SSc can have PAH alone, ILD alone, or both. But in reality, most patients have some level of fibrosis, or scarring — ILD comprises a group of disorders leading to progressive scarring of the lung.

It is unknown whether a more severe ILD, which causes a significant restriction to lung vessels, can influence the development of PAH. It is also not known whether PAH would develop through a different mechanism in those with a milder interstitial disease.

 Researchers compared SSc patients with PAH or ILD using a panel of genetic biomarkers. A set of 69 genes was chosen based on correlation with SSc-PAH, seen in a prior study, and biological relevance.

This is important to understand because SSc patients may differ at the molecular level, and therefore “may require separate clinical classifications in trials, molecular diagnostics, and therapeutic targets,” researchers said.

The team examined the pattern of expression (turned-on/turned-off state) of those 69 genes in peripheral blood mononuclear cells (PBMCs) — an important group of white blood cells that includes monocytes and lymphocytes. These cells are widely used in research and clinical testing, as they are useful for studying many biological aspects.

PBMCs were analyzed in 10 healthy controls, 39 SSc patients without pulmonary hypertension, and 21 SSc-PAH patients.

Eleven patients had ILD, defined as those with signs of fibrosis on computed tomography scans of the chest and a significant restriction in lung capacity (forced vital capacity, FVC, lower than 70% predicted).

From the 69 genes screened, five — S100P, TIMP1, CCL2, THBS1 and CD8B1 — were selected for further analysis as their expression was significantly correlated with PAH, and they are likely involved in the biology of the disease.

Results revealed that male sex and CD8B1 profile (namely lower levels) were correlated with PAH, both in the presence or absence of ILD. In contrast, THBS1 profile (higher levels) was related to PAH only when ILD patients were excluded from the analysis.

These results suggested that THBS1 “appears to be an important mediator in the development of the PAH-predominant” type, researchers said.

THBS1 instructs for the production of a small protein important for the activation of a immunological pathway called TGF-β signaling.

Of note, S100P and CD8B1 profiles in SSc-early PAH patients (considered as those having borderline elevated pulmonary arterial pressure), followed the trend of the SSc-PAH group, when compared with healthy controls and non-PAH patients.

This result suggests that the activation of some genes may be changed early in the course of PAH.

“Many gene expression changes occur early in the disease course, potentially allowing early detection,” the researchers said. “In conclusion, SSc-PAH and SSc-ILD have similar, but distinct, gene expression profiles.”