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Meta-Analysis
. 2024 Jan 11:14:1334361.
doi: 10.3389/fimmu.2023.1334361. eCollection 2023.

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

Zong Jiang #  1 , Xin Cai #  2 , Xiaoling Yao  1 , Shaoqin Zhang  2 , Weiya Lan  1 , Zexu Jin  2 , Fang Tang  3 , Wukai Ma  3 , Xueming Yao  3 , Changming Chen  3 , Tianzuo Lan  2
Affiliations
Meta-Analysis

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

Zong Jiang et al. Front Immunol. .

Abstract

Objective: Osteoarthritis (OA) is the most prevalent joint disease globally, serving as a primary cause of pain and disability. However, the pathological processes underlying OA remain incompletely understood. Several studies have noted an association between cytokines and OA, yet the causal link between them remains ambiguous. This study aims to identify cytokines potentially causally related to OA using Mendelian randomization (MR) analysis, informing early clinical diagnosis and treatment decisions.

Methods: We conducted a genome-wide association study (GWAS) on 12 OA traits involving 177,517 cases and 649,173 controls from 9 international cohorts. For discovery MR analysis, we used 103 cytokines from two European populations as instrumental variables (IVs). Concurrently, another European population OA GWAS database (36,185 cases and 135,185 controls) was used to replicate MR analysis, employing the inverse variance weighted (IVW) method as the primary analytic approach. Additional methods tested included MR Egger, Weighted median, and Weighted mode. We merged the MR findings through meta-analysis. Heterogeneity testing, level pleiotropy testing (MR Egger intercept test and MRPRESSO), and sensitivity analysis via Leave One Out (LOO) were conducted to verify result robustness. Lastly, reverse MR analysis was performed.

Results: The meta-analysis merger revealed a correlation between CX3CL1 cycle levels and increased OA risk (OR=1.070, 95% CI: 1.040-1.110; P<0.010). We also observed associations between MCP4 (OR=0.930, 95% CI: 0.890-0.970; P<0.010) and CCL25 (OR=0.930, 95% CI: 0.890-0.970; P<0.010) with reduced OA risk. The sensitivity analysis results corroborate the robustness of these findings.

Conclusion: Our MR analysis indicates a potential causal relationship between CX3CL1, MCP4, CCL25, and OA risk changes. Further research is warranted to explore the influence of cytokines on OA development.

Keywords: Mendelian randomization; bidirectional; cytokines; meta analysis; osteoarthritis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study design and workflow of this study.
Figure 2
Figure 2
Heatmap of Different MR Analysis Methods for Cytokines and the Risk of Osteoarthritis.
Figure 3
Figure 3
Forest map of cytokines and the risk of osteoarthritis.
Figure 4
Figure 4
Forest Map of MR Analysis of Cytokines and Risk of Osteoarthritis (replication).
Figure 5
Figure 5
Forest Map of combined results of osteoarthritis risk from the meta-analysis.
See this image and copyright information in PMC

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