scholarly journals A Novel Multi-network Approach Reveals Tissue-specific Cellular Modulators of Fibrosis in Systemic Sclerosis, Pulmonary Fibrosis and Pulmonary Arterial Hypertension

2016 ◽  
Author(s):  
Jaclyn N Taroni ◽  
Casey S Greene ◽  
Viktor Martyanov ◽  
Tammara A Wood ◽  
Romy Christmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Fibrosis ◽  
Arterial Hypertension ◽  
Gene Expression Signature ◽  
Alternative Activation ◽  
Tissue Specific ◽  
Expression Signature ◽  
Pulmonary Arterial

We have used integrative genomics to determine if a common molecular mechanism underlies different clinical manifestations in systemic sclerosis (SSc), and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH). We identified a common pathogenic gene expression signature - an immune-fibrotic axis-indicative of pro-fibrotic macrophages in multiple affected tissues (skin, lung, esophagus and PBMCs) of SSc, PF, and PAH. We used this disease-associated signature to query tissue-specific functional genomic networks. This allowed us to identify common and tissue-specific pathology of SSc and related conditions. We rigorously contrasted the lung- and skin-specific gene-gene interaction networks to identify a distinct lung resident macrophage signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct macrophages alternative activation transcriptional programs in SSc-PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. Our results suggest that the innate immune system is central to SSc disease processes, but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.

scholarly journals Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease

2018 ◽  
Vol 3 (3) ◽  
pp. 242-248 ◽  
Author(s):  
Matthew Moll ◽  
Romy B Christmann ◽  
Yuqing Zhang ◽  
Michael L Whitfield ◽  
Yu Mei Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Interstitial Lung Disease ◽  
Arterial Hypertension ◽  
Lung Disease ◽  
Expression Profiles ◽  
Area Under The Curve ◽  
Gene Expression Profiles ◽  
Pulmonary Arterial

Objective: Pulmonary arterial hypertension and interstitial lung disease are major causes of mortality in systemic sclerosis. We used a previously identified microarray biomarker to determine whether systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease patients demonstrate distinct gene expression profiles. Methods: Peripheral blood mononuclear cells were collected from healthy controls ( n = 10), systemic sclerosis patients without pulmonary hypertension (systemic sclerosis-no pulmonary arterial hypertension, n = 39), and systemic sclerosis-pulmonary arterial hypertension patients ( n = 21; mean pulmonary arterial pressure ≥25, pulmonary capillary wedge pressure ≤15, and pulmonary vascular resistance ≥3 Wood units) diagnosed by right heart catheterization. Systemic sclerosis-interstitial lung disease patients were defined as those with evidence of fibrosis on chest computed tomography and significant restriction (forced vital capacity <70% predicted, n = 11). Systemic sclerosis-pulmonary arterial hypertension biomarker included 69 genes selected by unbiased statistical screening of three publicly available microarray studies. RNA levels were measured by NanoString Technologies. Gene expression levels that were significantly correlated with pulmonary arterial hypertension (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model. Results: When interstitial lung disease patients were included ( n = 64), four genes (S100P, CD8B1, CCL2, and TIMP1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.83). Without interstitial lung disease patients ( n = 53), two genes (THBS1 and CD8B1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.80). When examining systemic sclerosis patients with borderline elevated pulmonary pressures (mean pulmonary arterial pressure = 21–24 mmHg), gene expression changes closely resembled the systemic sclerosis-pulmonary arterial hypertension group, except for THBS1. Conclusion: Systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease have similar but distinct gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing early detection. THBS1 appears to be an important mediator in the development of pulmonary arterial hypertension-predominant phenotype. Further prospective investigation is warranted.

scholarly journals HLA Markers for Poor Prognosis in Systemic Sclerosis Brazilian Patients

2013 ◽  
Vol 35 ◽  
pp. 73-78 ◽  
Author(s):  
Ana Paula Toledo Del Rio ◽  
Zoraida Sachetto ◽  
Percival Degrava Sampaio-Barros ◽  
João Francisco Marques-Neto ◽  
Ana Carolina Santos Londe ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Fibrosis ◽  
Arterial Hypertension ◽  
Polymerase Chain Reaction Amplification ◽  
Clinical Manifestations ◽  
Case Series ◽  
Delta Method ◽  
Hla Typing ◽  
Pulmonary Arterial

Objectives. The aim of this study was to evaluate human leukocyte antigen (HLA) involvement in the disease expression and poor prognostic clinical features (pulmonary fibrosis and pulmonary arterial hypertension) in patients diagnosed with systemic sclerosis (SSc) in a multiethnic population.Methods. SSc patients followed up between 2008 and 2011 were included, and clinical data were obtained through records review. Molecular HLA typing was performed (polymerase chain reaction amplification technique using specific primer sequences). The statistical analysis involved Fisher’s exact test and Pearson's corrected chi-square test.P  values≤0.05were considered significant. The delta method was used to estimate the variance of the prevalence ratio (PR).Results. A total of 141 patients (120 women and 21 men) with SSc were studied, including 33.3% with diffuse cutaneous SSc (dcSSc), 62.4% with limited cutaneous SSc (lcSSc), and 4.3% with sine scleroderma. Pulmonary fibrosis was present in 61 patients (43.3%), and the HLA-A*30 and DQB1*04 alleles were related to susceptibility. In contrast, the HLA-DRB1*01 and DQB1*05 alleles were protective. Pulmonary arterial hypertension was diagnosed in 19 patients (13.5%) and was associated with HLA-B*35 and C*04; in contrast, C*03 seemed to be protective.Conclusions. Our current study documents the association of some classes I and II HLA alleles with the most severe clinical manifestations in a multiethnic case series. Our findings differed slightly from the previous data in other populations.

scholarly journals Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension

2011 ◽  
Vol 63 (6) ◽  
pp. 1718-1728 ◽  
Author(s):  
Romy B. Christmann ◽  
Everett Hayes ◽  
Sarah Pendergrass ◽  
Cristina Padilla ◽  
Giuseppina Farina ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Alternative Activation ◽  
Pulmonary Arterial

scholarly journals Candidate Genes Identified in Systemic Sclerosis-Related Pulmonary Arterial Hypertension Were Associated with Immunity, Inflammation, and Cytokines

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Zhixiao Xu ◽  
Jiaxing Ruan ◽  
Lingyun Pan ◽  
Chengshui Chen
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Candidate Genes ◽  
Coexpression Network ◽  
Gene Coexpression Network ◽  
Hub Genes ◽  
Gene Coexpression ◽  
Pulmonary Arterial

Background. Pulmonary complications of systemic sclerosis (SSc), including pulmonary arterial hypertension (PAH), are the leading causes of patient death. However, the precise molecular mechanisms of its etiology are unclear. This study’s objective was to identify the candidate genes involved in the progression of SSc-PAH and investigate the genes' function. Methods. The gene expression profiles of GSE33463 were obtained from the Gene Expression Omnibus (GEO) database. A free-scale gene coexpression network was constructed using the weighted gene coexpression network analysis (WGCNA) to explore the association between gene sets and clinical features and identify candidate biomarkers. Then, gene ontology analysis was performed. A second dataset was used, GSE19617, to validate the hub genes. The verified hub genes’ potential function was further explored using gene set enrichment analysis (GSEA). Results. Through average link-level clustering, a total of seven modules were classified. A total of 938 hub genes were identified in the key module, and the key module’s function mainly enriched was related to chemokine activities. Subsequently, four candidate genes, BTG3, CCR2, RAB10, and TMEM60, were filtered. The expression levels of these four hub genes were consistent in the GSE19617 and GSE33463 datasets. We plotted the ROC curve of the hub genes (all AUC > 0.70 ). Furthermore, the results of the GSEA for hub genes were correlated with complement and inflammatory responses. Conclusions. The hub genes (BTG3, CCR2, RAB10, and TMEM60) performed well in distinguishing the SSc-PAH patients from controls, and some biological functions, related to immunity, inflammation, and cytokines, might pave the way for follow-up studies on the diagnosis and treatment of SSc-PAH.

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