Combining single-cell analysis and Mendelian randomization to elucidate the molecular mechanisms of fibronectin-related genes in multiple sclerosis

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.