Unveiling causal pathways in autoimmune diseases: a multi-omics approach.

Abstract

Autoimmune diseases (ADs), such as Graves' disease (GD), Hashimoto's thyroiditis (HT), psoriasis, systemic lupus erythematosus (SLE), and type 1 diabetes (T1D), involve complex immune and inflammatory responses. This study employed Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data to examine the causal relationships among 91 circulating inflammatory proteins, 41 cytokines, 211 gut microbiota, and 731 immune cell traits in relation to ADs. Additionally, we integrated mediation and bioinformatics analyses, including protein-protein interaction (PPI) networks, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Subnetwork discovery and key protein identification were performed using the Molecular Complex Detection (MCODE) plugin, alongside colocalization analysis and drug target exploration to identify potential mechanisms. MR analysis identified significant causal relationships between various circulating inflammatory proteins, cytokines, gut microbiota species, immune cells, and ADs, with certain relationships retaining significance after false discovery rate (FDR) correction. Mediation analysis demonstrated that inflammatory proteins mediate pathogenic pathways linking immune cells to psoriasis and gut microbiota to Hashimoto's thyroiditis. PPI and bioinformatics analyses highlighted 22 key proteins involved in ADs, while subnetwork analysis identified 15 central proteins. Fms-related tyrosine kinase 3 ligand (FLT3LG) exhibited strong colocalization evidence. Molecular docking confirmed several proteins as viable drug targets. This comprehensive multi-omics study advances our understanding of ADs, identifies novel therapeutic targets, and offers valuable insights for developing new treatment strategies.