Exploring the relationship between tumor necrosis factor-α, interleukin-6, interleukin-12 and gout: a bidirectional Mendelian randomization study
10.3760/cma.j.cn141217-20240922-00276
- VernacularTitle:探究TNF-α IL-6 IL-12与痛风的相关性：基于双向孟德尔随机化研究
- Author:
Luwei LI
1
;
Wenjie YANG
1
Author Information
1. 中山大学附属第一医院广西医院（广西壮族自治区人民医院东院）风湿免疫科，南宁 530025
- Publication Type:Journal Article
- Keywords:
Tumor necrosis factor-α;
Interleukin-6;
Interleukin-12;
Refractory gout;
Mendelian randomization
- From:
Chinese Journal of Rheumatology
2025;29(4):312-319
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To verify the causal relationship between tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-12 (IL-12) and gout using Mendelian randomization (MR) analysis. The findings are expected to provide insights into whether TNF-α, IL-6, IL-12 antagonists and other biological agents can be applied in the treatment of refractory gout (RG) in clinical practice.Methods:This study conducted a two-sample MR using publicly available summary statistics from an independent European ancestry cohort. For the data on TNF-α, IL-6, and IL-12, data were retrieved from the GWAS catalog database. For the gout data, to avoid confounding, the FinnGen database was used. The analysis was performed using R4.3.2 software. The statistical significance threshold was set at P<5×10 -5. Linkage disequilibrium (LDA was set to R2>0.001) was removed, and strongly correlated and independent single nucleotide polymorphism (SNP) loci were selected for analysis. Five methods were used for analysis: inverse variance weighting (IVW), MR Egger, weighted median, simple mode, and weighted mode. IVW was used as the main analysis method. When pleiotropy was present, MR-Egger estimates were considered more persuasive than IVW estimates, so MR-Egger was taken as the primary analysis method. Cochran′s Q test and MR-Egger intercept test were used to assess heterogeneity and pleiotropy. The leave-one-out method was used to test the stability of MR results by systematically excluding instrumental variables (IVs). Finally, a reverse MR analysis of gout and TNF-α, IL-6, IL-12 was conducted. Results:The IVW-MR, MR Egger, weighted median, simple mode, and weighted mode analyses showed no causal relationship between IL-6, IL-12, and gout (all P>0.05). Cochran′s Q test and MR-Egger intercept test results showed no significant heterogeneity or horizontal pleiotropy affecting causal estimates (all P>0.05). The leave-one-out test indicated stable results. MR-Egger analysis showed a weak causal relationship between TNF-α and gout [ OR(95% CI)=0.892 (0.812, 0.979), b=-0.113, P=0.021], while the other methods (IVW-MR, weighted median, simple mode, weighted mode) showed no causal relationship between TNF-α and gout (all P>0.05). Cochran′s Q test indicated no heterogeneity affecting causal estimates ( P>0.05), but MR-Egger intercept test suggested the presence of horizontal pleiotropy affecting causal estimates ( P<0.05). The reverse MR analysis of gout and TNF-α, IL-6, IL-12 showed no causal relationships (all P>0.05). No significant heterogeneity or horizontal pleiotropy affected causal estimates (all P>0.05), and the leave-one-out test indicated that the results were stable. Conclusion:MR analysis suggests that there is no causal relationship between IL-6, IL-12, and gout, but TNF-α may have a weak causal relationship with gout. More accurate and solid evidence are needed from further prospective randomized controlled trials.
