Mendelian randomization analysis to identify potential drug targets for osteoarthritis

Abstract

Background: Osteoarthritis (OA) is a prevalent chronic joint disease for which there is a lack of effective treatments. In this study, we used Mendelian randomization analysis to identify circulating proteins that are causally associated with OA-related traits, providing important insights into potential drug targets for OA.

Method: Causal associations between 1553 circulating proteins and five OA-related traits were assessed in large-scale two-sample MR analyses using Wald ratio or inverse variance weighting, and the results were corrected for Bonferroni. In addition, sensitivity analyses were performed to validate the reliability of the MR results, including reverse MR analysis and Steiger filtering to ensure the causal direction between circulating proteins and OA; Bayesian co-localization and phenotypic scanning were used to eliminate confounding effects and horizontal pleiotropy. External validation was performed to exclude incidental findings using novel plasma protein quantitative trait loci. Finally, the online analysis tool Enrichr was utilized to screen drugs and molecular docking was performed to predict binding modes and energies between proteins and drugs to identify the most stable and likely binding modes and drugs.

Result: Four proteins were ultimately found to be reliably and causally associated with three OA-related features: DNAJB12 and USP8 were associated with knee OA, IL12B with spinal OA, and RGMB with thumb OA. The ORs for the above proteins were 1.51 (95% CI, 1.26-1.81), 1.72 (95% CI, 1.42-2.08), 0.87 (95% CI, 0.81-0.92), and 0.59 (95% CI, 0.47-0.75), respectively. Drug-predicting small molecules (doxazosin, XEN 103, and montelukast) that simultaneously target three proteins, DNAJB12, USP8, and IL12B, docked well.

Conclusion: Based on our comprehensive analysis, we can draw the conclusion that there is a causal relationship between the genetic levels of DNAJB12, USP8, IL12B, and RGMB and the risk of respective OA.They may be potential options for OA screening and prevention in clinical practice. They can also serve as candidate molecules for future mechanism exploration and drug target selection.

Fig 1. Schematic representation of the study design.

(A) The figure depicts the three key assumptions in the MR analysis. (B) Overall analysis process.

Fig 2. Visualization of molecular docking results.

(A) Binding affinity of proteins to small molecule drugs, (B) 3D and 2D visualisation of DNAJB12 docking with Doxazosin, (C) 3D and 2D visualisation of USP8 docking with XEN 103, (D) 3D and 2D visualisation of IL12B docking with Montelukast.