Regulator combinations identify systemic sclerosis patients with more severe disease
| Autor: | Diana M. Toledo, Monique Hinchcliff, Monica Yang, Jennifer M. Franks, Yue Wang, Michael L. Whitfield, Tammara A. Wood |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Vital capacity Bioinformatics Pulmonary Fibrosis Autoimmune diseases Regulator Autoimmunity Dermatology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Fibrosis Gene expression Humans Medicine Gene Regulatory Networks Skin Scleroderma Systemic integumentary system business.industry Organ dysfunction Interstitial lung disease Computational Biology General Medicine medicine.disease 030104 developmental biology 030220 oncology & carcinogenesis Cohort Immunology medicine.symptom Transcriptome business Algorithms Biomarkers Research Article |
| Zdroj: | JCI Insight, Vol 5, Iss 17 (2020) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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. An association between the activation of regulators, gene expression subsets, and clinical variables identifies systemic sclerosis patients with more severe disease. |
| Databáze: | OpenAIRE |
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