Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis:...

Area of Science:

• Genetics
• Epidemiology
• Immunology

Background:

• Rheumatoid arthritis (RA) is a widespread chronic inflammatory condition.
• Environmental factors like air pollution and smoking are suspected RA risk factors.
• Causal links and mechanisms between exposures and RA remain unclear.

Purpose of the Study:

• To investigate causal relationships between air pollution, smoking, and RA.
• To explore genetic correlations and mediating pathways.
• To analyze associations with seropositive RA (SPRA) and seronegative RA (SNRA).

Main Methods:

• Bidirectional two-sample Mendelian randomization (MR) using large-scale GWAS data.
• Linkage disequilibrium score regression (LDSC) for genetic correlations.
• Mediation analysis for iron metabolism and urinary biomarkers.

Main Results:

• Genetically predicted lifetime smoking intensity showed an 85% increased RA risk.
• A causal link was found between smoking and SPRA, but not SNRA.
• C-reactive protein mediated smoking's effect on RA (18.23%) and SPRA (32.45%).

Conclusions:

• Smoking has a causal impact on RA development, particularly SPRA.
• C-reactive protein mediates smoking-induced RA risk via inflammatory pathways.
• Findings support public health strategies to reduce smoking exposure for RA prevention.