Insulin-like growth factor binding protein 7 as a candidate biomarker for systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease clinically characterised by skin and internal organs fibrosis with high mortality. However, the pathogenesis of SSc is still controversial and the effect of the current treatment is far from satisfactory. We aimed to find out novel candidate genes related to the pathological process in SSc. METHODS: In this study, the weighted correlation network analysis (WGCNA) was conducted to identify the key module and hub genes most related to SSc in GSE58095, a microarray dataset from the Gene Expression Omnibus (GEO) database. Also, the key module was analysed by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then we validated hub genes in other datasets (GSE32413, GSE125362, GSE45485, GSE76885, GSE95065). The serum of 37 patients with SSc and 25 healthy control subjects (HCs) were recruited and detected by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Five interested genes (IGFBP7, LRRC32, STMN2, C1QTNF5, CPXM1) were up-regulated in SSc microarray datasets from the GEO. And the level of serum IGFBP7, which encodes a secreted protein, was upregulated in SSc patients-also in dcSSc patients and SSc with ILD patients. CONCLUSIONS: Among the five interested genes, the IGFBP7 was a novel candidate gene for SSc and may be served as potential target and early biomarker for accurate treatment, which also provides further insights into the pathogenesis of SSc at the molecular level.

Identification and Validation of Key Genes Associated With Systemic Sclerosis-Related Pulmonary Hypertension.

Systemic sclerosis-associated with pulmonary arterial hypertension (SSc-PAH) is still a major cause of SSc related deaths. Early diagnosis and prompt treatment are crucial to reduce the mortality of patients with SSc-PAH. To screen the candidate biomarkers and potential therapeutic targets for SSc-PAH, we analyzed the data set (GSE33463 and GSE19617) for confirming key genes in peripheral blood mononuclear cells from SSc-PAH patients. A total of 105 SSc patients from gene expression omnibus (GEO) were included as discovery cohort (n = 69) and duplication cohort (n = 36) for screening hub genes by weighted gene co-expression network analysis (WGCNA). Furthermore, an independent validation cohort (n = 40), including healthy controls, SSc and SSc-PAH patients, was used for further validation by quantitative real-time polymerase chain reaction. The results showed that four key genes, including IFIT2, IFIT3, RSAD2, and PARP14, may serve as potential biomarkers in SSc-PAH. Also, they could be independent risk factors for SSc-PAH. In conclusion, the four key genes can be expected to become the potential therapeutic targets and early biomarkers for accurate therapy and diagnosis of SSc-PAH in the future, which also provides promising insights into the pathogenesis of SSc-PAH at the molecular level.

Increased serum calpain activity is associated with HMGB1 levels in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) or scleroderma is an intractable autoimmune disorder that affects multiple organs. The objectives were to investigate clinical correlations of serum calpain activity and high mobility group box 1 (HMGB1) levels with immunological and clinical traits. METHODS: A total of 31 patients with SSc, 20 age- and gender-matched healthy control subjects (HC), and 10 patients with other connective tissue diseases (CTD) were recruited in the study. We measured serum calpain activity and HMGB1 levels and analyzed the datasets (GSE40839, GSE48149, GSE76808, GSE81292, GSE33463, and GSE58095) from Gene Expression Omnibus (GEO) database to explore the potential mechanism by which calpain exerts its function through bioinformatics methods. RESULTS: Serum calpain activity was significantly increased in patients with SSc compared with those in HC and in patients with CTD and was correlated with serum HMGB1 levels, modified Rodnan skin score, erythrocyte sedimentation rate, mean platelet volume, and plateletcrit. Notably, serum calpain activity and HMGB1 levels in SSc patients with interstitial lung disease (ILD) were significantly higher than those in SSc patients without ILD. Serum calpain activity and HMGB1 levels could be the independent risk factors for SSc-ILD and novel biomarkers in patients with SSc. CONCLUSION: This is the first study that reports increased serum calpain activity and the correlation between calpain and HMGB1 in patients with SSc or SSc-ILD. The serum calpain activity and HMGB1 levels may serve as measures of ILD in patients with SSc. Also, calpain and HMGB1 could be potential therapeutic targets for patients with SSc or SSc-ILD in the future.