Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder that results in skin fibrosis, autoantibody production and internal organ dysfunction. We previously identified four ‘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 find regulator activity scores can reproduce the intrinsic molecular subsets with distinct sets of regulators identified for inflammatory, fibroproliferative and normal-like samples. Regulators most highly correlated with modified Rodnan skin score (MRSS) also varied by intrinsic subset. We identify a subgroup of fibroproliferative/inflammatory SSc patients with more severe pathophenotypes. We further identify a subgroup of SSc patients that had higher MRSS and increased likelihood of interstitial lung disease. Using an independent cohort, we show this group was most likely to show forced vital capacity decline over a period of 36 – 54 months. Our results demonstrate an association between the activation of regulators, gene expression subsets and clinical variables that can identify SSc patients with more severe disease.


Yue Wang, Jennifer M. Franks, Monica Yang, Diana M. Toledo, Tammara A. Wood, Monique Hinchcliff, Michael L. Whitfield


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