Systematic druggable genome-wide Mendelian randomization identifies novel therapeutic targets or repurposing opportunities for rheumatoid arthritis

Background Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease. Currently, a complete cure for RA is still unavailable. Mendelian randomization (MR) has emerged as a valuable tool for identifying potential therapeutic targets or drug repurposing opportunities for certain diseases. Therefore, our aim was to identify novel effective targets or drug repurposing opportunities for RA and analyze their mechanisms and potential side effects. Methods A MR integrating the identified druggable genes was used to evaluate the causal effects of druggable gene cis-expression quantitative trait loci (cis-eQTLs) on RA, while additional RA cohort was employed for validation. Colocalization analysis was performed to determine the probability of shared causal variants between the identified targets and RA. The protein-protein interaction network analysis was conducted to explore associations between the identified druggable genes and current RA drug targets. The MR and colocalization analyses were used to assess the potential side effects of the identified targets in RA treatment. Results Nine druggable genes (TYK2, PTPN22, ATP2A1, APOM, RXRB, NOTCH4, HLA-DRA, CCR6, and CTLA4) showed significant MR results in both the training cohort (p<1.99E-05) and validation cohort (p<0.0025). Colocalization analysis indicated that cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and RA (PP.H4.abf=0.98), as well as C-C motif chemokine receptor 6 (CCR6) and RA (PP.H4.abf=0.99), shared the same causal variant. Hence, these two genes were identified as the final therapeutic targets. Furthermore, CTLA4 and CCR6 interacted with the current RA drug targets. Subsequent MR analysis revealed that genetically proxied activation of CTLA4 and inhibition of CCR6 might decrease the risk of hypothyroidism but increase the risk of malignant skin neoplasm. Additionally, genetically proxied activation of CTLA4 may also reduce the risk of type 1 diabetes. Conclusions This study supports the idea that targeting the activation of CTLA4 and the inhibition of CCR6 may reduce the risk of RA with fewer side effects, and highlights the potential of CTLA4 and CCR6 as promising druggable targets for RA treatment.