Causal Relationship Between Plasma Protein-to-Protein Ratios and Rheumatoid Arthritis: A Proteome-wide Mendelian...

The causal relevance of circulating plasma protein-to-protein ratios (PPRs) in Rheumatoid Arthritis (RA) remains unclear. We employed Mendelian Randomization (MR) to investigate this relationship.

This study utilized summary data of ratio quantitative trait loci (rQTLs) for 2,821 circulating PPRs from the GWAS Catalog and two RA-related GWAS datasets (FinnGen and GWAS Catalog). Causal estimates were obtained using various Mendelian randomization (MR) methods, including IVW and MR-Egger regression. Significant PPRs were further analyzed via protein-protein interaction (PPI), functional enrichment, and druggability assessments. Key genes were validated using qPCR.

Fifteen candidate PPRs with consistent directional effects, and nine core PPRs, achieved statistical significance in both datasets. Protein-protein interaction (PPI) network analysis revealed involvement of these proteins in various biological processes. Gene Ontology (GO) analysis indicated roles in immune response and protein binding, while KEGG pathway analysis showed enrichment in Toll-like receptor signaling pathways. Friends analysis identified UBAC1 as a key gene, and seven PPR-associated proteins were found to be druggable. qPCR validation confirmed differential expression of UBAC1, CD40, ITGB5, and GLOD4.

Our findings establish a robust genetic causal link between specific PPRs and RA, moving beyond association to suggest potential etiology. Integrated analyses prioritize UBAC1, CD40, ITGB5, and GLOD4 as key contributors to RA pathogenesis, with functional enrichment indicating their involvement in immune and inflammatory pathways. The druggability of several implicated proteins underscores the translational potential of these results.

This study used MR to establish a causal relationship between plasma PPRs and RA risk. UBAC1, CD40, ITGB5, and GLOD4 may play key roles in the pathogenesis of RA.