Genome-wide association study identifies toll-like receptor four protein-mediated metabolic remodelling affecting gout pathogenesis
Bibliographic Data
| ID | 23311639 |
|---|---|
| Authors | Yutong Li (0000-0001-8653-6698), Zhaofeng Yi, Xuan Dong (0000-0001-7697-4299), Ruixu Sun, Liangmeng Gao, Yuanning Zheng (0000-0002-0018-3252), Hongwei Liu (0000-0001-6471-131X) |
| Year | 2026 |
| Volume | 16 |
| Pages | 04268-04268 |
| Publication date | 2026-07-31 |
| Peer Reviewed | Yes |
| Open Access | Yes |
| Type | ARTICLE |
| Venue | Journal of Global Health (JOURNAL) |
| Journal identifiers | ISSN: 2047-2978 • E-ISSN: 2047-2986 |
| Publisher | International Society of Global Health (PUBLISHER • GB) |
| DOI | 10.7189/jogh.16.04268 |
| PMID | 42533613 |
| OpenAlex | W7171996492 |
| Language | EN |
| References cited | 109 |
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.
Candidate gene · Druggability · Genetic association · Genome-wide association study · Gout · Linkage Disequilibrium · Obesity · Observational study · Pathogenesis · Gout, Hyperuricemia, Uric Acid · Inflammasome and immune disorders · Thyroid Disorders and Treatments
Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement
Spirometric Reference Values from a Sample of the General U.S. Population
Reading Mendelian randomisation studies
Journal of Global Health’s Guidelines for Reporting Analyses of Big Data Repositories Open to the Public (GRABDROP)
Terminalia chebula Retz. extract relieves gout arthritis by inhibiting xanthine oxidase, the uric acid transporter, and NLRP3 inflammasome activation
| Citation velocity | historical |
|---|---|
| Highly cited | No |