Rheumatoid factor production is genetically and molecularly distinct from rheumatoid arthritis
Mehmet Hocaoğlu, Amr H. Sawalha
Mehmet Hocaoğlu, Amr H. Sawalha
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Clinical Research and Public Health Autoimmunity Genetics

Rheumatoid factor production is genetically and molecularly distinct from rheumatoid arthritis

Abstract

BACKGROUND Rheumatoid 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.METHODS A 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.RESULTS RF 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.CONCLUSION RF production is governed by HLA class II and B cell regulatory loci, associated with mucosal inflammation, and genetically and molecularly distinct from RA.FUNDING This study was supported by the Rheumatoid Arthritis Research Program Grant from the Arthritis Foundation.

Authors

Mehmet Hocaoğlu, Amr H. Sawalha

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Figure 5

Comparative proteomics profiling of asymptomatic RF production and RF+ RA.

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Comparative proteomics profiling of asymptomatic RF production and RF+ R...
(A) Scatter plot of protein-level logFCs in asymptomatic RF+ versus RF– HCs (x axis) versus RF+ RA versus RF+ without RA (y axis). Proteins were classified using a combined significance criterion requiring both an adjusted P value of less than 0.01 and |logFC| of greater than 0.05 in each comparison. Points are colored according to the significance category: RF versus HCs only (significant only in RF vs. HCs), RA versus RF only (significant only in RA vs. RF), both (significant in both comparisons), and not significant. Proteins that were top hits defined by absolute logFC within single-comparison groups and by Euclidean distance for proteins significant in both comparisons are annotated in the plot. (B) Heatmap of proteins showing logFC values for RF versus HCs and RA versus RF comparisons. Proteins are grouped by the direction of change across comparisons and are ranked within direction groups by their logFC magnitude. Up to 10 proteins with the most statistically significant change in each direction group are depicted. “Up” and “Down” represent upregulation and downregulation in the respective analyses, while “NS” represents no statistically significant change. Direction group names such as “Up → Up” or “Up → Down” represent the direction of change for the depicted protein in RF versus HCs and RA versus RF comparisons, respectively. Cell colors represent the logFC magnitude and direction (centered at 0).