Exploration of Circadian Clock-Related Genes in the Pathogenesis of Psoriatic Arthritis to Identify Potential Therapeutic Targets From Multi-Omics Insight: A Mendelian Randomization Study.

BACKGROUND

Circadian rhythms have been shown to play a significant role in the etiology and progression of immune-related morbidities, including cancer and autoimmune diseases. As an autoimmune disorder, psoriatic arthritis (PsA) has been underexplored in the context of circadian rhythms. This study aimed to explore the relationship between circadian rhythm and PsA.

METHODS

We conducted a Summary-data-based Mendelian randomization (SMR) analysis, obtaining summary data on gene methylation, expression, and protein abundance levels of circadian clock-related genes (CRGs) from European ancestry individuals, with a total of 1749 genes selected from the GeneCards database using "biological clock" as the search term. The discovery cohort was obtained from the GWAS catalog database, and the replication cohort was obtained from the FinnGen database. Candidate genes related to circadian rhythm and PsA were identified through research, and their pharmacological potential and molecular docking were further validated as drug targets.

RESULTS

After integrating multi-omics data, we identified 11 methylation sites in three genes (HLA-DQB1, ITPR3, and GABBR1) of CRGs that were causally related to PsA, and the effects produced were not consistent. The three gene expressions of CRGs (IL4, HLA-DQB1, and OPI-AIS5) were related to PsA. At the protein level, we identified three proteins (GCKR, STAT3, and CSNK2B) of CRGs related to PsA. The top 20 drug candidates underwent drug prediction screening, resulting in the identification of 12 compounds that demonstrated effective outcomes with three (HLA-DQB1, STAT3, and IL-4) specific therapeutic targets through molecular docking.

CONCLUSION

This study suggests altered expression of circadian clock genes and proteins, including HLA-DQB1, ITPR3, GABBR1, IL4, OIP5-AS1, GCKR, CSNK2B, and STAT3, as factors contributing to the increased risk of PsA.