Objective:

To identify circulating proteins associated with primary knee osteoarthritis (PKOA) and explore their potential as therapeutic targets.

Approach:

• Study Design: A two-sample Mendelian randomization (MR) study was conducted using data from deCODE Genetics and the FinnGen study.
• Data Sources: Included 4,907 plasma proteins from 35,559 individuals and PKOA genetic association data from 18,563 cases and 363,345 controls.
• Analytical Methods: Single nucleotide polymorphisms were used as instrumental variables, with sensitivity analyses and multiple testing corrections applied.
• Biological Validation: Western blotting and enzyme-linked immunosorbent assay were performed to validate the expression of prioritized proteins.

Key Findings:

• Higher levels of TXNDC12 are associated with increased risk of PKOA (OR = 1.38, 95% CI: 1.27–1.50, P = 9.33 × 10–15).
• GDF2 is associated with reduced risk of PKOA (OR = 0.93, 95% CI: 0.89–0.98, P = 4.17 × 10–2), but requires further validation.
• TXNDC12 remained significant after multiple testing correction, while GDF2 met the FDR threshold only.
• Network analyses identified 21 functionally related genes to TXNDC12 and GDF2.
• Preliminary analyses showed increased TXNDC12 and decreased GDF2 expression in PKOA model mice.

Interpretation:

TXNDC12 is identified as a genetically supported plasma protein associated with PKOA, while GDF2 is a candidate needing further validation.

Limitations:

• The study relies on genetic associations and may not establish direct causation.
• GDF2 findings are considered hypothesis-generating and require additional validation.

Conclusion:

The study provides preliminary evidence linking TXNDC12 and GDF2 to PKOA.