Plasma proteins and rheumatoid arthritis: A Mendelian randomization analysis

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory systemic autoimmune disease with incompletely understood etiology, causing substantial global disease burden. This study aimed to identify plasma proteins associated with RA using Mendelian randomization (MR) of large-scale plasma proteomics, providing potential biomarkers and therapeutic targets for early diagnosis and personalized treatment. We conducted a large-scale plasma proteome MR study using genetic data from 58,293 Europeans (14,361 RA patients and 43,932 controls) in a genome-wide association study. Plasma protein quantitative trait loci data for 4907 adaptors in 35,559 Icelanders were obtained from Ferkingstad et al. (2021). MR methods included MR-Egger, weighted median, inverse-variance weighting, Wald ratio, simple, and weighted models. Heterogeneity was assessed with Cochran Q test; horizontal pleiotropy was evaluated using the MR-Egger intercept and MR-PRESSO global test. Sensitivity was assessed by leave-one-out analysis. Analyses of gene ontology (describing biological functions), Kyoto Encyclopedia of Genes and Genomes (mapping functional pathways), and protein-protein interaction (identifying molecular interaction networks) were also performed. MR identified associations between 4907 plasma proteins and RA. Using an exploratory false discovery rate < 0.20, 11 novel plasma proteins were significantly associated. For example, genetically higher C2 levels increased RA risk (odds ratio per 1-standard deviation = 1.38; 95% confidence interval: 1.21-1.58), whereas higher USP25 decreased risk (odds ratio per 1-standard deviation = 0.61; 95% confidence interval: 0.48-0.79). C2, HS3ST3A1, MAPK3, PRSS57, and TNFAIP8 are potential risk factors; AIF1, ATF6, CXCL16, HMBS, DNASE1L2, and USP25 are protective. Inverse MR confirmed ATF6's negative correlation with RA risk. Gene ontology analysis indicated involvement in monocyte migration, leukocyte chemotaxis, and cytotaxis. Kyoto Encyclopedia of Genes an Genomes analysis revealed enrichment in pertussis, IL-17, and chemokine signaling pathways. Protein-protein interaction analysis by GeneMANIA identified 20 additional interacting genes and 416 links. This study highlights novel plasma proteins and pathways causally linked to RA, warranting functional and clinical follow-up to clarify biological roles and translational potential.