An integrated multi-omics analysis identifies protein biomarkers and potential drug targets for psoriatic arthritis

Abstract

Psoriatic arthritis (PsA) is a complex, chronic immune-mediated inflammatory arthropathy that currently lacks definitive biomarkers and treatment targets. Identifying biomarkers and treatment targets is urgently needed for effectively managing PsA. Here, we conducted a multi-omics approach to identify protein biomarkers and potential drug targets for psoriatic arthritis. Proteome-wide Mendelian randomization (MR) analysis revealed seven plasma protein biomarkers significantly associated with PsA. Specifically, genetically predicted lower levels of NEO1 were linked to an increased PsA risk, whereas the remaining six proteins (IL23R, ERAP2, IFNLR1, KIR2DL3, CLSTN3, and POLR2F) exhibited a positive association with PsA risk. PPI analysis further supported these findings. Notably, druggability assessment revealed that scopoletin and esculetin were the two most significant drugs associated with ERAP2. Single-cell RNA-seq analysis revealed expression of IL23R, ERAP2, CLSTN3, and POLR2F in distinct T-cell subgroups of PBMCs derived from PsA patients. Furthermore, phenome-wide association studies (PheWAS) analysis assessed the potential side effects and safety as potential drug targets. Interestingly, experimental evidence showed that IFNLR1 expression is significantly upregulated under simulated inflammatory conditions. This study employed proteome-wide mendelian randomization to identify seven plasma proteins associated with PsA, including IL23R, ERAP2 and IFNLR1, offering potential insights for personalized PsA treatment strategies.