Uncovering novel metabolic and inflammatory pathways in gout using Mendelian randomization.

Objective: This study aimed to systematically evaluate the causal roles of circulating metabolites and inflammatory markers in gout using Mendelian randomization (MR), to uncover underlying pathogenic mechanisms and inform clinical interventions.

Methods: Genome-wide association studies (GWAS) data from 14 824 individuals of European ancestry were utilized, covering 1400 blood metabolites and 91 inflammatory markers. Gout data were obtained from a Finnish GWAS cohort. Causal relationships between metabolites, inflammatory markers, and gout were assessed using MR methods such as inverse variance weighted (IVW), MR-Egger, and weighted median approaches. Sensitivity analyses including Cochran's Q test, MR-Egger intercept, and MR-PRESSO were conducted to ensure robustness.

Results: Our MR analysis identified five metabolites with significant causal associations with gout, with the following quantified findings: Hexanoylglutamine (OR = 1.28, 95% CI: 1.17-1.41, P = 8.56 × 10-8), Glycocholenate sulfate (OR = 0.87, 95% CI: 0.82-0.92, P = 2.52 × 10-6), and Phenylacetylcarnitine (OR = 1.26, 95% CI: 1.09-1.44, P = .001) were all significantly associated with gout risk. The SLCO1B1 (PPH4 = 0.92) and GCKR (PPH4 = 0.99) loci were found to influence gout through metabolic regulation. Additionally, three inflammatory markers (CST5, FGF21, and MMP1) were causally linked to gout. Specifically, FGF21 increased the phosphate-to-mannose ratio (OR = 1.30, 95% CI: 1.17-1.46, P = 3.70 × 10-6), while MMP1 elevated glycocholenate sulfate and hexanoylglutamine levels, contributing to gout development.

Conclusion: This study highlights key metabolites and inflammatory markers in gout pathogenesis, suggesting new therapeutic targets, particularly at the SLCO1B1 and GCKR loci, to improve gout management and patient outcomes.