Genetic Evidence and Immunological Mechanisms Underlying the Link between Air Pollution and Rheumatic Arthropathies

Abstract Accumulating epidemiological evidence suggests associations between ambient air pollution and rheumatic arthropathies, yet the underlying biological mechanisms remain elusive. We conducted a comprehensive genetic investigation linking five major air pollutants (PM2.5, PM2.5–10, PM10, NO2, NOx) with ten clinically defined rheumatic arthropathies. Using integrative genetic approaches, we systematically evaluated associations with over 800 immune and inflammatory traits to uncover potential mediators and mechanistic pathways. Analyses included variant-level overlap, immune trait profiling, and pathway-based sensitivity checks. Higher genetically proxied PM2.5 exposure was associated with increased risk of gout, rheumatoid arthritis, monoarthritis, and systemic lupus erythematosus. NO2 exposure showed a significant association with juvenile arthritis. Colocalization analysis identified a shared causal locus (rs12203592) between PM2.5 exposure and knee osteoarthritis, suggesting a disease-specific genetic architecture. Mediation analysis identified six significant pollutant–mediator–disease pathways involving five immune/inflammatory markers, including myeloid- and lymphocyte-associated surface proteins and matrix metalloproteinase-1. This study provides novel genomic and immunological insights into how ambient air pollution contributes to the development of rheumatic arthropathies through immune–inflammatory mechanisms. Our findings underscore the relevance of environmental exposures in immune-mediated joint diseases and support the One Health framework linking environmental and human health.