{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T21:05:51Z","timestamp":1770757551811,"version":"3.50.0"},"reference-count":70,"publisher":"S. Karger AG","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"},{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int Arch Allergy Immunol"],"abstract":"<jats:p>Introduction: The upstream immunological drivers of rheumatoid arthritis (RA) and their downstream proteomic effectors remain incompletely resolved. We implemented an integrated, two-layer Mendelian randomization (MR) atlas to systematically map genetically supported causal influences across immune traits and plasma proteins, nominating candidates relevant to RA pathogenesis. Methods: In layer 1, we evaluated the causal relevance of 731 immune-cell phenotypes to RA using two-sample MR with stringent instrument filters and multiple-testing correction. In layer 2, we integrated cis-pQTLs of 4,907 plasma proteins with RA through MR and Bayesian colocalization, followed by replication in the UK Biobank, reverse MR, and transcriptomic validation in three independent RA datasets. Drug-target mapping was followed by in silico docking as a pipeline proof-of-concept rather than functional validation. Results: Layer-1 implicated myeloid antigen-presenting were risk-enhancing, whereas adenosinergic (CD39-axis) and RAGE-axis traits showed protective directionality. Layer-2 convergently prioritized thrombin\/prothrombin (F2), indicating a coagulation-inflammation coupling as a causal RA driver, coherent with known thrombo-inflammatory amplification and excess cardiovascular risk in RA. Transcriptomic validation demonstrated consistent, directionally concordant upregulation of BRD2 and MICB across all three independent RA cohorts. As a benchmark of the computational pipeline, bortezomib (BTZ) to F2 suggested structural compatibility without implying druggability (binding energy: \u22125.53 kcal\u00b7mol\u22121). Conclusions: Genetic evidence supports an immune\u2192coagulation causal axis in RA, nominating thrombin\/F2 as a translational node and motivating a dual therapeutic rationale: suppressing procoagulant inflammation while enhancing genetically protective pathways (e.g., CD39+ and sRAGE). These findings provide a genetically anchored prioritization framework and motivate subsequent experimental and trial-proximal validation.<\/jats:p>","DOI":"10.1159\/000550107","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T17:00:56Z","timestamp":1766163656000},"page":"1-18","source":"Crossref","is-referenced-by-count":0,"title":["A Genetic Atlas of Rheumatoid Arthritis Integrating Immune Traits and Plasma Proteins Identifies Genetically Supported Candidate Effectors along the Coagulation-Inflammation 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