Combining single-cell analysis and Mendelian randomization to elucidate the molecular mechanisms of
Na Zhao1, Mayinuer Maimaiti2, Hongyan Li2
1Department of Graduate School, Xinjiang Medical University, Urumqi, Xinjiang, China.
Abstract:
Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease, and the association between the fibronectin-related genes (FRGs) and MS is unclear. We aimed to clarify the molecular mechanism and causality of FRGs in MS by single-cell combining Mendelian randomization (MR) analysis. The cell types identified by single-cell analysis with GSE193770 dataset were sorted into high- and low-expression groups based on FRG levels. According to differentially expressed genes from key cells, MR was employed to obtain key genes and their causal relationships. Additionally, immune infiltration analysis and functional enrichment were performed to explore the significance of key genes, with RT-qPCR validating their expression. Six cell types were identified, with natural killer (NK) cells being pivotal. Four key genes were revealed from MR: CAT, RGS10, S100A10, and CD247. Univariable MR showed CAT and RGS10 as protective factors, while S100A10 and CD247 were risk factors. Multivariable MR further emphasized CD247's significance. Expression validation using the GSE41850 dataset and RT-qPCR confirmed underexpression of CAT and CD247 in MS samples, and overexpression of S100A10. Immune infiltration analysis showed significant positive correlations between CD247 and Tregs, resting CD4 memory T cells, and T follicular helper cells, while CAT showed significant negative correlations with activated and resting NK cells. This study explored the causal relationship between the key genes CAT, RGS10, S100A10, and CD247 and MS progression and provided novel perspectives into the application of FRGs for the treatment and prognosis of MS.
Insights
This study identifies four key fibronectin-related genes (FRGs) involved in multiple sclerosis (MS) progression. CD247 and S100A10 are identified as risk factors, while CAT and RGS10 may offer protection against MS.
Area of Science:
- Immunology
- Genetics
- Computational Biology
Background:
- Multiple sclerosis (MS) is an autoimmune disease impacting the central nervous system.
- The role of fibronectin-related genes (FRGs) in MS pathogenesis remains largely uncharacterized.
- Understanding genetic associations is crucial for developing targeted MS therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms and causal relationships between FRGs and MS.
- To identify key FRGs influencing MS development and progression.
- To explore the potential of FRGs as therapeutic targets or prognostic markers for MS.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) to identify cell types and gene expression patterns in MS.
- Mendelian randomization (MR) analysis to establish causal links between FRGs and MS.
- Immune infiltration analysis and functional enrichment to understand gene significance.
- RT-qPCR for experimental validation of gene expression levels.
Main Results:
- Natural killer (NK) cells were identified as a pivotal cell type in MS.
- Four key FRGs (CAT, RGS10, S100A10, CD247) were identified through MR analysis.
- CAT and RGS10 showed protective effects, while S100A10 and CD247 indicated increased MS risk.
- CD247 demonstrated significant correlations with regulatory T cells (Tregs) and T follicular helper cells.
Conclusions:
- This study establishes causal relationships between specific FRGs and MS, highlighting CD247 and S100A10 as risk factors and CAT/RGS10 as protective.
- Findings provide novel insights into the genetic underpinnings of MS and suggest potential therapeutic avenues targeting FRGs.
- The research underscores the utility of integrating single-cell and MR analyses for complex disease research.
More Related Videos
07:05TGF-β-mediated Endothelial to Mesenchymal Transition EndMT and the Functional Assessment of EndMT Effectors using CRISPR/Cas9 Gene Editing
Published on: February 26, 2021
06:24Multiplexed Analysis of Retinal Gene Expression and Chromatin Accessibility Using scRNA-Seq and scATAC-Seq
Published on: March 12, 2021
