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. 2023 Apr 3;62(4):1662-1668.
doi: 10.1093/rheumatology/keac492.

Longitudinal global transcriptomic profiling of preclinical systemic sclerosis reveals molecular changes associated with disease progression

Chiara Bellocchi  1   2 , Lorenzo Beretta  2 , Xuan Wang  3 , Marka A Lyons  4 , Maurizio Marchini  1 , Maurizio Lorini  1 , Vincenzo Carbonelli  1 , Nicola Montano  1 , Shervin Assassi  4
Affiliations

Longitudinal global transcriptomic profiling of preclinical systemic sclerosis reveals molecular changes associated with disease progression

Chiara Bellocchi et al. Rheumatology (Oxford). .

Abstract

Objective: To investigate peripheral blood cell (PBCs) global gene expression profile of SSc at its preclinical stage (PreSSc) and to characterize the molecular changes associated with progression to a definite disease over time.

Material and methods: Clinical data and PBCs of 33 participants with PreSSc and 16 healthy controls (HCs) were collected at baseline and follow-up (mean 4.2 years). Global gene expression profiling was conducted by RNA sequencing and a modular analysis was performed.

Results: Comparison of baseline PreSSc to HCs revealed 2889 differentially expressed genes. Interferon signalling was the only activated pathway among top over-represented pathways. Moreover, 10 modules were significantly decreased in PreSSc samples (related to lymphoid lineage, cytotoxic/NK cell, and erythropoiesis) in comparison to HCs. At follow-up, 14 subjects (42.4%) presented signs of progression (evolving PreSSc) and 19 remained in stable preclinical stage (stable PreSSc). Progression was not associated with baseline clinical features or baseline PBC transcript modules. At follow-up stable PreSSc normalized their down-regulated cytotoxic/NK cell and protein synthesis modules while evolving PreSSc kept a down-regulation of cytotoxic/NK cell and protein synthesis modules. Transcript level changes of follow-up vs baseline in stable PreSSc vs evolving PreSSc showed 549 differentially expressed transcripts (336 up and 213 down) with upregulation of the EIF2 Signalling pathway.

Conclusions: Participants with PreSSc had a distinct gene expression profile indicating that molecular differences at a transcriptomic level are already present in the preclinical stages of SSc. Furthermore, a reduced NK signature in PBCs was related to SSc progression over time.

Keywords: disease progression; gene expression; modular analysis; preclinical SSc.

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Figures

Figure 1.
Figure 1.
The top ten overrepresented canonical pathways (A) Top 10 overrepresented canonical pathway in comparison of baseline PreSSc samples to healthy controls; (B) Top 10 overrepresented Canonical Pathway in comparison of follow-up to baseline sample changes in stable vs in evolving PreSSc groups
Figure 2.
Figure 2.
The Cytotoxic/NK cell module scores in study groups. * indicates statistically significant differences in QuSAGE analysis. The follow-up vs baseline analyses compared each follow-up sample to the baseline samples of the same patient
See this image and copyright information in PMC

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