The functional study of core genes in systemic lupus erythematosus obtained through WGCNA analysis and two- sample Mendelian randomization research

Abstract

Abstract Background：Systemic lupus erythematosus is a chronic autoimmune disease characterized by systemic inflammation. The underlying mechanisms of the disease are not yet clear, resulting in limited treatment options. The aim of this study is to investigate the potential core genes of systemic lupus erythematosus and evaluate their clinical applications in predicting the disease. Method：We employed differential expression analysis and weighted gene co-expression network analysis (WGCNA) to explore novel susceptibility modules and core genes associated with systemic lupus erythematosus. Further investigation of these core genes was carried out using KEGG and GO analyses to examine their potential roles. We established column line plot models and ROC curves to evaluate the diagnostic performance of the core genes. Additionally, we investigated the correlation between the core genes and immune infiltration. Finally, based on genome-wide association studies, we conducted a Mendelian randomization study to determine the causal effect of GYPB on systemic lupus erythematosus. Results：We used the WGCNA method to construct a gene co-expression network and identified the most relevant modules related to systemic lupus erythematosus (SLE), as well as 144 overlapping key genes. GO and KEGG pathway enrichment analysis revealed that these core genes are closely associated with pathways such as DNA polymerase complex, astral microtubule and transferase complex, Malaria, and Porphyrin metabolism. Through analysis using Cytoscape software, we found that the top 10 upregulated genes with high scores were SLC4A1, EPB42, FECH, GYPB, ALAS2, AHSP, GATA1, KLF1, SNCA, and DMTN. Additionally, we observed that the column line graph model performed well in predicting the risk of systemic lupus erythematosus, and the ROC curve indicated its effectiveness for diagnosis. In the end, we confirmed a causal relationship between the top five ranked core genes and immune cell infiltration in systemic lupus erythematosus. Additionally, in the inverse-variance weighted analysis, we found a negative correlation between GYPB and systemic lupus erythematosus, with an odds ratio (OR) of 0.620 (95% confidence interval = 0.4056-0.948, p=0.02). Conclusion：We used WGCNA to construct a gene co-expression network and identified the core genes associated with systemic lupus erythematosus. These core genes help uncover the molecular mechanisms of systemic lupus erythematosus and enable further investigation into potential therapeutic targets.