Rheumatoid factor production is genetically and molecularly distinct from rheumatoid arthritis

BACKGROUNDRheumatoid factor (RF) autoantibodies are highly prevalent, yet the molecular determinants of RF development and its progression to rheumatoid arthritis (RA) remain poorly understood. Here, we define the genetic, phenotypic, and molecular architecture of RF and its progression to RA.METHODSA total of 469,036 UK Biobank participants with RF testing and 76 Allen Institute for Immunology-University of California, San Diego-University of Colorado Transition to Rheumatoid Arthritis (ALTRA) cohort individuals were studied. Phenome-wide association studies (PheWAS), GWAS, and proteome-wide association studies (PWAS) compared RF+ individuals who did not have autoimmune disease with RF- control individuals. Single-cell RNA-seq enabled pseudobulk differential expression and cytokine signature enrichment analyses.RESULTSRF seroprevalence was 9.3% and longitudinally stable in 94.5% of individuals. PheWAS identified 48 significant associations, led by chronic viral hepatitis (OR 4.8), hypersensitivity pneumonitis (OR 3.6), bronchiectasis (OR 1.9), and COPD (OR 1.4). GWAS of 24,216 RF+ individuals revealed 29 independent loci; the strongest signal was in the extended HLA region (OR 1.45, P = 5.4 × 10-221). Non-HLA loci converged on B cell homeostasis genes (ETS1, BACH2, PAX5, TNFRSF13B, FCGR2A). RF+ individuals did not carry elevated RA polygenic risk. Proteomics profiling identified 153 differentially abundant proteins enriched for humoral immunity and IFN-induced chemokines, with 79% showing dose response relationships across titers. Progression to RA involved a shift toward activating tissue-damaging inflammatory pathways rather than amplification of the RF signature. Single-cell transcriptomics of RF+ individuals without RA localized dysregulation to memory B cells, with downregulation of inhibitory genes (FCGR2B, BACH2, FOXP1) and upregulation of activation markers.CONCLUSIONRF production is governed by HLA class II and B cell regulatory loci, associated with mucosal inflammation, and genetically and molecularly distinct from RA.FUNDINGThis study was supported by the Rheumatoid Arthritis Research Program Grant from the Arthritis Foundation.