Genetic influences of the effect of circulating inflammatory cytokines on osteoarthritis in humans

The causal relationship between inflammatory cytokines and Osteoarthritis (OA) has not been well investigated. This study investigated the causal role of inflammatory cytokines in the risk of OA and total joint arthroplasty using the Mendelian randomization (MR) method.Single nucleotide polymorphisms (SNPs) robustly associated with inflammatory cytokines were used as instrumental variables. The inverse-variance weighted (IVW) method with false discovery rate (FDR) adjusted P-value (q-value) for multiple comparisons were used as the main MR method to estimate causal effects based on the summary-level data for OA (knee and hip OA, respectively) and total joint arthroplasty (TJA). Sensitivity analyses validated the robustness of the results and ensured the absence of heterogeneity and horizontal pleiotropy.After FDR adjustment, macrophage colony-stimulating factor (MCSF) and vascular endothelial growth factor (VEGF) were identified as causally associated with knee OA (MCSF, odds ratio [OR]: 1.16, 95% confidence interval [CI]: 1.09-1.23, q = 5.05 × 10-5; VEGF, OR: 1.09, 95% CI: 1.04-1.15, q = 0.011). We also observed that genetically predicted MCSF and VEGF were positively associated with the risk of TJA, and MCP3 was negatively associated with for the risk of TJA, although the effects seem fairly modest. Sensitivity analysis further excluded the influence of heterogeneity and horizontal pleiotropy.Inflammatory cytokines, namely MCSF and VEGF, were causally associated with knee OA, which could enhance our understanding of inflammation in OA pathology.