Association between circulating inflammatory proteins and gout: A Mendelian randomization study

Abstract

Clinical studies have consistently demonstrated that inflammation is a critical factor in the pathophysiology and progression of gout. This study aims to explore the causal relationship between CIPs and gout, utilizing MR in conjunction with meta-analyses. We utilized genetic data pertaining to gout from the GWAS which involved 3576 cases and 147,221 control participants. A total of 132 CIPs were extracted from the GWAS data to identify SNPs associated with gout. The primary analytical approach was the IVW method. Sensitivity analyses indicated no pleiotropy or heterogeneity. The IVW results revealed that several CIPs were associated with gout in European populations. The analysis results indicate that FGF-21, MMP-1, G-CSF, and IFN-γ are involved in the pathogenesis of gout, and gout may influence the expression of CXCL1, IL-1Ra, and TNF-α. Consequently, targeted research focusing on specific CIPs could provide a promising strategy for the treatment and prevention of gout, offering potential therapeutic targets for the underlying inflammatory mechanisms of the disease.

Keywords: Mendelian randomization; bidirectional; circulating inflammatory proteins; gout; meta-analysis.

Figure 1.

Bidirectional MR research flowchart for CIPs and gout. This figure elucidates the 3 foundational assumptions of MR: (1) Relevance: SNPs robustly associated with exposure, independence, and exclusion restriction; (2) Independence: SNPs not associated with confounders; (3) Exclusion restriction: SNPs only associated with outcome through exposure. CIPs = circulating inflammatory proteins, IVs = instrumental variables, SNPs = single nucleotide polymorphisms, MR = Mendelian randomization.

Figure 2.

The positive results of the forward MR analysis conducted with the Inverse variance weighted, MR-Egger, Weighted median, Simple mode, and Weighted mode method. FGF21 = Fibroblast Growth Factor 21, MMP-1 = Matrix Metalloproteinases-1, nsnp = the number of single-nucleotide polymorphisms used in the analysis, OR = odds ratio.

Figure 3.

Scatter plots of the causal effects of CIPs associated SNPs on gout. (A) FGF21, Fibroblast Growth Factor 21; (B) MMP-1, Matrix metalloproteinase-1; (C) G-CSF, Granulocyte Colony-Stimulating Factor; (D) IFN-γ, Interferon-gamma; (E) TGF-_α, Transforming Growth Factor Alpha. CIPs = circulating inflammatory proteins, SNPs = single nucleotide polymorphisms.

Figure 4.

Circular heatmap of forward MR analysis. The circular heatmap, from outer to inner layers, represents the P values obtained from 5 MR methods (IVW, MR Egger, Weighted median, Simple mode, Weighted mode), with the innermost layer depicting the OR values obtained from the IVW method. IVW = Inverse variance weighted.

Figure 5.

The positive results of the reverse MR analysis conducted with the Inverse variance weighted, MR-Egger, Weighted median, Simple mode, and Weighted mode method. CXCL1 = CXC motif chemokine ligand 1, IL-1Ra = Interleukin 1 Receptor Antagonistm, nsnp = the number of single-nucleotide polymorphisms used in the analysis, OR = odds ratio, TNF-α = Tumor Necrosis Factor-alpha.

Figure 6.

Scatter plots of the causal effects of gout associated SNPs on CIPs. (A) CXCL1, CXC motif chemokine ligand 1; (B) IL-1Ra, Interleukin 1 Receptor Antagonist; (C) TNF-α, Tumor Necrosis Factor-alpha. CIPs = circulating inflammatory proteins, SNPs = single nucleotide polymorphisms.

Figure 7.

Circular heatmap of reverse MR analysis. The circular heatmap, from outer to inner layers, represents the P values obtained from 5 MR methods (IVW, MR Egger, Weighted median, Simple mode, Weighted mode), with the innermost layer depicting the OR values obtained from the IVW method. IVW = Inverse variance weighted.

Figure 8.

Forest plot of the relationship between gout and CXCL1 based on meta-analysis results from the reverse MR analysis. CXCL1 = CXC motif chemokine ligand 1, MR = Mendelian randomization, nsnp = the number of single-nucleotide polymorphisms used in the analysis, OR = odds ratio.