Mendelian Randomisation Uncovers Causal Immune-Metabolic Networks in Osteoarthritis: Insights from Immune Cell and...

The synergistic effect of immune dysfunction and metabolic disorder has gradually become a research focus in osteoarthritis (OA).

This study investigated the causal role of metabolites mediating immune cells in OA through a Mendelian randomisation (MR) study.

A mediation MR framework was employed, integrating data from 731 immune cell phenotypes, 1,400 metabolites and OA genome-wide association studies. Genetic instrumental variables strongly associated with immune phenotypes such as 'HLA DR+ CD4+ lymphocytes' (F ≥ 10, P < 5 × 10⁻⁸) were selected, and causal effects were validated using inverse-variance weighted (IVW), MR-Egger, and MR-pleiotropy residual sum and outlier methods, with metabolite-mediated proportions calculated.

MR initially identified immune cells and metabolites causally associated with OA. Subsequent mediation analysis indicated that HLA DR+ CD4+ lymphocytes mediated 19.5% of OA risk through leucine levels (P = 0.030), involving mTORC1 signalling activation and epigenetic regulation. CD25 on CD45RA+ CD4 non-Treg cells exacerbated oxidative stress via S-carboxyethylcysteine (mediation proportion 12.5%, P = 0.033), whereas HLA DR+ NK cells exhibited protective effects through suberate (mediation proportion: -9.89%, P = 0.048). Sensitivity analyses confirmed the robustness of the findings.

This study establishes for the first time a genetic-level immune-metabolic-OA causal network, demonstrating causal links between immune cells and OA and highlighting the critical mediating role of metabolites.