Implications of TLR4 Polymorphisms for Precision Therapeutics in Gram-negative Infections: An Ethnogeographic-Stratified Meta-Analysis.

PURPOSE: To quantify definitively the impact of loss-of-function variants of Toll-like receptor 4 (TLR4) (Asp299Gly, rs4986790 and Thr399Ile, rs4986791) on the susceptibility to, and mortality from, Gram-negative bacterial infections, and to evaluate how these associations are modulated by ethnogeographic factors.

METHODS

This systematic review and meta-analysis was prospectively registered (PROSPERO CRD420251155764) in accordance with PRISMA and MOOSE guidelines. In order to assess correlations between TLR4 polymorphisms and Gram-negative infection outcomes, we searched 6 electronic databases for observational studies (January 1, 2016 to December 31, 2025). Random-effects models were used to create pooled odds ratios (ORs) and hazard ratios (HRs). We examined pre-specified ethnogeographic subgroups and used formal meta-regression.

FINDINGS: Of the 6,198 records examined, 29 studies involving 9,196 participants were included. Carriage of the Asp299Gly variant significantly heightened susceptibility to infection (OR: 2.05; 95% CI: 1.72-2.45) and infection-related mortality (HR: 1.78; 95% CI: 1.52-2.08). The Thr399Ile variant was also associated with an increased risk of infection. Moderate heterogeneity (I² = 48.3%) was effectively mitigated by ethnogeographic stratification (intra-subgroup I² = 0-25%; between-subgroup Q-test p = 0.021). The strongest associations were observed in Middle Eastern and European populations.

IMPLICATIONS: TLR4 polymorphisms are significant risk factors for adverse outcomes in Gram-negative infections, with the level of risk being greatly affected by the ethnogeographic ancestry of the host. These findings provide a robust epidemiological basis for future precision medicine research, including TLR4 genotype-stratified clinical trials of immunomodulatory agents.