Multi-GWAS analysis illuminates druggable targets for rheumatoid arthritis.

Objective: Despite the treatment choices for rheumatoid arthritis (RA) increasing, there remain unmet preventive and therapeutic needs for RA. This study aimed to identify effective drug target genes to reduce RA risk through the multi-genome-wide association studies analysis.

Methods: A Mendelian randomization (MR) analysis was conducted to investigate the causal effects of druggable expression quantitative trait loci (eQTLs) in the blood on RA. Colocalization analysis assessed the shared causal genetic variants between the identified drug target genes and RA. Furthermore, eQTLs analysis of B and T cells in different states provided valuable insights into gene regulation in RA at a single-cell resolution. Summary-data-based MR (SMR) was performed to explore the casual relationship between the methylation levels of druggable genes and RA. The impact of druggable genes on RA biomarkers and other autoimmune diseases with available genome-wide association data was also evaluated.

Results: Five drug target genes (CCR6, CTLA4, EDN3, FCRL3, STAT4) were identified to be causally related to RA. At single-cell resolution, CCR6 in Th1/17, Th17, and CD4 follicular helper T cells (TFH), EDN3 in Th1/17, Th17, and Th2, and FCRL3 in active naive CD8 and naive B cells were found to be associated with RA. The SMR analyses revealed that seven methylation probes of CCR6 and thirteen methylation probes of EDN3 were associated with RA. Further investigation showed no noticeable side effect of identified druggable genes.

Conclusion: This study identifies five promising druggable target genes for RA treatment, offering valuable insights for prioritizing drug development strategies in RA.