# Mediating Role of the ANGPTL3/TFPI Protein Ratio in Regulating T-Cell Surface Glycoprotein CD5 Levels on Knee Osteoarthritis (KOA): A Mendelian Randomization Study

## TL;DR

This study finds that the ANGPTL3/TFPI protein ratio mediates how T-cell surface glycoprotein CD5 levels affect knee osteoarthritis, suggesting a new target for treatment.

## Contribution

The study identifies the ANGPTL3/TFPI ratio as a novel mediator linking CD5 levels to KOA progression.

## Key findings

- T-cell surface glycoprotein CD5 levels were negatively associated with knee osteoarthritis (KOA).
- The ANGPTL3/TFPI protein ratio mediates the effect of CD5 levels on KOA progression.
- Variations in inflammatory proteins like CD5 and CXCL9 influence KOA through genetic and protein-level interactions.

## Abstract

This study utilized Mendelian randomization (MR) to investigate the impact of inflammatory proteins on knee osteoarthritis (KOA), measured using the ratio of protein levels (rQTLs). The primary objective was to identify potential intervention targets to mitigate KOA progression. Data from 2821 rQTLs, 91 inflammatory proteins, and KOA-related genetic variations were obtained through genome-wide association studies (GWAS). Bidirectional MR identified rQTLs with unidirectional causal relationships with KOA. Further analyses included false discovery rate (FDR) correction, colocalization, and mediation analysis. Two inflammatory proteins were found to be associated with KOA: T-cell surface glycoprotein CD5 [OR (95% CI) = 0.867 (0.760–0.990), PIVW = 0.035] and C-X-C motif chemokine 9 [OR (95% CI) = 1.150 (1.001–1.320), PIVW = 0.048]. Variations in their levels influenced rQTLs, producing differential effects on KOA. Specifically, rQTL-ANGPTL3/TFPI (human recombinant angiopoietin-like protein 3/Tissue factor pathway inhibitor) was identified as a mediator in the effect of T-cell surface glycoprotein CD5 levels on KOA. T-cell surface glycoprotein CD5 levels were negatively correlated with rQTL-ANGPTL3/TFPI (β1 = −0.084), while rQTL-ANGPTL3/TFPI was positively correlated with KOA (β2 = 0.159). These findings align with the total effect, where T-cell surface glycoprotein CD5 levels were negatively associated with KOA (β = −0.143). Thus, rQTL-ANGPTL3/TFPI may serve as a reliable mediator in the pathway through which T-cell surface glycoprotein CD5 levels affect KOA. This mediator may not only represent a potential therapeutic target but also serve as a biomarker for assessing KOA treatment efficacy, offering a novel direction for KOA diagnosis and management.