Systemic Sclerosis-Associated PAH Genomic Signature Differs From ILD

DNA helix
DNA helix
Systemic sclerosis-associated pulmonary hypertension and systemic sclerosis-associated interstitial lung disease exhibit similar but distinct gene expression profiles.

Patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) and patients with SSc-associated interstitial lung disease (ILD) exhibit similar but distinct gene expression profiles, according to the results of a retrospective cohort study conducted at the Boston University Medical Center. Findings from the analysis were published in the Journal of Scleroderma and Related Disorders.

Investigators sought to examine whether patients with SSc-PAH and those with SSc-ILD express distinct genomic signatures. Participants enrolled in the study included the following groups: SSc without PAH (n=39), SSc and PAH (n=25), and healthy controls (n=10). Duration of SSc was measured from onset of the first non-Raynaud phenomenon symptom. Patients with SSc were diagnosed with PAH by right heart catheterization: mean pulmonary arterial pressure ≥25 mm Hg, pulmonary arterial wedge pressure ≤15 mm Hg, and pulmonary vascular resistance ≥3 Wood units.

Significant ILD (n=11) was diagnosed by predicted forced vital capacity <70% and review of chest computed tomography to ensure the presence of significant fibrosis (ie, reticulations, ground glass opacities, honeycombing, and septal thickening) and no alternative explanation for the restriction (SSc-PAH [n=3] and SSc-noPAH [n=8]). Blood was obtained from both healthy controls and patients on the day of catheterization or within 3 months. Samples were centrifuged, peripheral blood mononuclear cells were isolated, and total RNA was extracted.

SSc-PAH biomarkers included 69 genes chosen by unbiased statistical screening of 3 publicly available microarray studies. RNA levels were measured using Nanostring technology. All gene expression levels significantly associated with PAH were chosen as inputs into a forward selection logistic regression model.

When patients with ILD were included (n=64), a total of 4 genes (S100P, CD8B1, CCL2, and TIMP1), along with male sex, were predictive of PAH with a high level of accuracy (area under the curve, 0.83). When patients with ILD were excluded (n=53), 2 genes (THBS1 and CD8B1), along with male sex, predicted PAH with a high level of accuracy (area under the curve, 0.80). When patients with SSc and borderline elevated pulmonary pressures (ie, mean pulmonary arterial pressure 21-24 mm Hg) were assessed, gene expression changes other than THBS1 closely resembled those of patients in the SSc-PAH group.

The investigators concluded that many gene expression changes take place early in SSc disease course, potentially allowing for earlier detection. THBS1 is apparently an important mediator in the development of the PAH-predominant phenotype. Additional prospective studies are warranted to further elucidate these findings.

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Moll M, Christmann RB, Zhang Y, et al. Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease. J Scleroderma Relat Disord. 2018;3(3):242-248.