Abstract
Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder that results in skin fibrosis, autoantibody production, and internal organ dysfunction. We previously identified 4 “intrinsic” subsets of SSc based upon skin gene expression that are found across organ systems. Gene expression regulators that underlie the SSc-intrinsic subsets, or are associated with clinical covariates, have not been systematically characterized. Here, we present a computational framework to calculate the activity scores of gene expression regulators and identify their associations with SSc clinical outcomes. We found that regulator activity scores can reproduce the intrinsic molecular subsets, with distinct sets of regulators identified for inflammatory, fibroproliferative, limited, and normal-like samples. Regulators most highly correlated with modified Rodnan skin score (MRSS) also varied by intrinsic subset. We identified subgroups of patients with fibroproliferative and inflammatory SSc with more severe pathophenotypes, such as higher MRSS and increased likelihood of interstitial lung disease (ILD). Using an independent cohort, we show that the group with more severe ILD was more likely to show forced vital capacity decline over a period of 36–54 months. Our results demonstrate an association among the activation of regulators, gene expression subsets, and clinical variables that can identify patients with SSc with more severe disease.
Highlights
We found that regulator activity scores can reproduce the intrinsic molecular subsets, with distinct sets of regulators identified for inflammatory, fibroproliferative, limited, and normal-like samples
Systemic sclerosis (SSc) is a heterogeneous autoimmune disease that results in the production of autoantibodies, skin fibrosis, and internal organ involvement [1]; the pattern and severity of skin and organ involvement varies across patients
The size of a node indicates its degree of connection, and different colors of nodes represent different categories. Besides those regulators that have specific correlation directions with modified Rodnan skin score (MRSS) (4 corners in Figure 4C), we found that the activities of paired box 3 (PAX3) and sex-determining region Y (SRY), as shown in dark red, were positively correlated with MRSS in both fibroproliferative and inflammatory samples
Summary
Systemic sclerosis (SSc) is a heterogeneous autoimmune disease that results in the production of autoantibodies, skin fibrosis, and internal organ involvement [1]; the pattern and severity of skin and organ involvement varies across patients. We have previously identified “intrinsic” subsets of SSc (fibroproliferative, inflammatory, limited, and normal-like) based upon skin gene expression [5,6,7] that may predict response to therapy [8, 9]. The regulators that underlie SSc and the association with clinical phenotypes have not been systematically investigated. The goals of these analyses were 2-fold: first, to identify regulators of gene expression, such as transcription factors (TFs) and miRNAs that are enriched in the SSc-intrinsic subsets and, second, to identify regulators that could identify patients with SSc with more severe skin and lung disease. Our reasoning is that the regulators, and the network of genes that they control, may be informative of pathological processes acting in SSc
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
