Genome-wide association study identifies toll-like receptor four protein-mediated metabolic remodelling affecting gout pathogenesis

Background: Obesity is a major risk factor for gout, but the biological mechanisms linking adiposity to crystal-driven inflammation remain largely unknown. Identifying genetic mediators of this relationship is crucial for developing targeted therapies. Methods: We conducted an integrative multi-omics study anchored by observational analysis of 9,700 adults from the National Health and Nutrition Examination Survey and focused on genetic causal inference using two-sample Mendelian randomisation (MR) with summary-level genome-wide association data, followed by systematic screening of druggable gene loci and multi-layered validation. Key candidates were validated through Bayesian colocalisation, protein-protein interaction network analysis, linkage disequilibrium score regression, and multivariable MR. Results: Both observational and MR analyses confirmed a positive dose-dependent relationship between body mass index and gout (odds ratio = 1.97; 95% confidence interval = 1.41, 2.75). Among 113 screened druggable genes, toll-like receptor 4 (TLR4) emerged as a genetically supported candidate mediator, with colocalisation indicating shared causal variants for both traits (posterior probability >0.75). Network analysis positioned TLR4 as a central hub in innate immune and metabolic inflammatory pathways, and multivariable MR indicated a BMI-independent effect of TLR4 on gout risk (β = 0.23, P = 0.011). Conclusions: This study provides human genetic evidence identifying TLR4 as a candidate mediator at the interface of obesity and gout. The findings highlight the importance of metabolic-immune crosstalk in gout pathogenesis and suggest TLR4 as a potential therapeutic target, warranting further functional validation.