Genetically predicted circulating levels of cytokines and the risk of osteoarthritis: A mendelian randomization study

Background: The association between inflammatory cytokines and osteoarthritis (OA) has been reported in several observational studies, but the causal relationship between these two remains unknown. Hence, we performed this two-sample Mendelian randomization (MR) to confirm the causal relationship between circulating levels of inflammatory factors and osteoarthritis risk. Method: We used genetic variants associated with cytokine circulation levels from a meta-analysis of genome-wide association studies (GWASs) in 8,293 Finns as instrumental variables and obtained OA data from the United Kingdom Biobank, including a total of 345,169 subjects of European ancestry (66,031 diagnosed OA cases and 279,138 controls). Inverse variance weighting (IVW), MR-Egger, Wald Ratio, weighted median, and MR multiplicity residual sums with outliers (MR-PRESSO) were used. Result: We found a causal relationship between circulating levels of macrophage inflammatory protein-1beta (MIP-1 beta) and risk of OA (OR = 0.998, 95% CI = 0.996-0.999p = 9.61 x 10(-5)); tumour necrosis factor beta (TNF-beta) was also causally associated with risk of OA (OR = 0.996,95%CI = 0.994-0.999, p = 0.002); finally we found a suggestive association between C-C motif chemokine ligand 5(CCL5, also called Rantes) and OA risk (OR = 1.013, 95%CI = 1.002-1.024,p = 0.016). Conclusion: Our findings offer promising leads for the development of new therapeutic targets in the treatment of osteoarthritis. By identifying the role of inflammatory cytokines in this debilitating condition through a genetic epidemiological approach, our study contributes to a better understanding of the underlying disease mechanisms. These insights may ultimately pave the way for more effective treatments that improve patient outcomes.

Automated summary

In this two-sample Mendelian randomization (MR) study, we confirmed a causal relationship between circulating levels of inflammatory factors and osteoarthritis risk. We used genetic variants associated with cytokine circulation levels as instrumental variables and obtained data from the United Kingdom Biobank. Through various analyses, we found causal associations between macrophage inflammatory protein-1beta (MIP-1 beta), tumour necrosis factor beta (TNF-beta), and osteoarthritis risk, as well as a suggestive association between C-C motif chemokine ligand 5(CCL5) and osteoarthritis risk. These findings have implications for the development of new therapeutic targets in osteoarthritis.