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

Abstract

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-1β) and risk of OA (OR = 0.998, 95% CI = 0.996–0.999p = 9.61 × 10−5); tumour necrosis factor beta (TNF-β) 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.

The causal effect of cytokine cycling levels on osteoarthritis: a bidirectional Mendelian randomized study

“…Previously, MR studies investigating the causal relationship between cytokines and OA identified links with MIP-1B, TNFB, and RANTS ( 58 ), aligning with our MR analysis results. Another study found a causal relationship between MCSF and VEGF and OA ( 19 ),yet these associations were not replicated in our MR and replication MR analyses.…”

Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study

“…In order to acquire credible instrumental variables, we had devised a series of rigorous procedures of quality control for single nucleotide polymorphisms (SNPs). First, we identified SNPs associated with inflammatory proteins that exhibited genome-wide significance at a threshold of P-value < 5×10-8 to ensure that instrumental variables could proxy for exposure ( 22 ). Second, employing a reference panel of European (EUR) populations from the 1000 Genomes project offered by OpenGWAS API ( https://gwas-api.mrcieu.ac.uk/ ) ( 23 ), we applied linkage disequilibrium-based clumping with an R 2 <0.001 threshold over a range of 10,000 kb to ensure the isolation of the instrumental variables.…”

The causal relationship between serum metabolites and the risk of psoriasis: a Mendelian randomization and meta-analysis study

“…Heterogeneity was tested by Cochran’s Q statistic where a P -value greater than 0.05 suggests an absence of heterogeneity ( 16 ). Pleiotropy can be evaluated using the MR-PRESSO test and the MR-Egger regression intercept; if the P -value for the MR-PRESSO global Test and the MR-Egger intercept are greater than 0.05, this suggests that pleiotropy is not present ( 17 , 18 ). It is worth noting that when the number of SNPs is insufficient (3 for MR-PRESSO, 2 for MR-Egger), pleiotropy test will not be performed.…”