Identification of Novel Biomarkers and Potential Therapeutic Targets for Systemic Sclerosis: An Integrated Analysis
Hanchao Li1, Qian Li1, Xiaoxin Chen2
1Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
Background:
Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease. This study aimed to identify novel biomarkers for SSc through an integrated analysis of plasma proteome-wide Mendelian randomization (MR) and transcriptome, as well as to explore the potential mechanisms.
Methods:
The data used were obtained from public databases. Initially, key plasma proteins causally associated with SSc were identified through a two-sample MR analysis. Subsequently, based on the key diseases related to both key plasma proteins (genes) and key drugs targeting these proteins (genes), phenotype scanning was conducted to predict potential adverse side effects of key plasma proteins (genes). Single-cell RNA sequencing (scRNA-seq) analysis was performed to identify key cell types in GSE138669 dataset. Differentially expressed genes (DEGs) within key cell types in SSc were intersected with genes encoding key plasma proteins to obtain candidate biomarkers, whose functions were subsequently explored. By analyzing candidate biomarker expression in GSE138669 and GSE181549 datasets, the biomarkers were identified. Further exploration included regulatory network, cellular heterogeneity, and cell trajectory analyses.
Results:
Initially, 106 plasma proteins (corresponding to 104 genes) were identified. It was revealed that targeting 12 key plasma proteins (like CD40LG) for treating SSc might lead to side effects related to specific key diseases (like mesothelioma). After recognizing epithelial cells and fibroblasts as key cell types, 8 candidate biomarkers associated with pathways like "proteasome" were identified. Notably, CCL19 and LOXL2 were identified as biomarkers, which exhibited elevated expression in SSc. Regulatory elements such as FOXL1 and hsa-miR-5001-5p were predicted to target biomarkers. Remarkably, differentiation stages of key cell type with heterogeneity and the biomarker expression patterns across these stages might be associated with SSc progression.
Conclusion:
CCL19 and LOXL2 were identified as novel biomarkers for SSc, providing insights into the exploration of the disease's pathogenesis and the development of new therapeutic targets.
