ArticlePloS one2014
The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 60 citations in OpenAlex.
- Association between TLR4 A299G polymorphism and pneumonia risk: a meta-analysis.Medical science monitor : international medical journal of experimental and clinical research · 2015Pooled it
- The Role of TLR2/TLR4 Receptors in Host Genetic Susceptibility to Recurrent Vulvovaginitis.Journal of fungi (Basel, Switzerland) · 2025Review
- Identification of novel amino acid variants in the Han Chinese population that impair toll-like receptor 4 signaling and confer hyporesponsiveness to lipopolysaccharide.Frontiers in immunology · 2025Article
- Allelic, Genotypic, and Haplotypic Analysis of Cytokine IL17A, IL17F, and Toll-like Receptor TLR4 Gene Polymorphisms in Metabolic-Dysfunction-Associated Steatotic Liver Disease: Insights from an Exploratory Study.Life (Basel, Switzerland) · 2024Article
- TLR4 Polymorphisms (T399I/D299G) Association with Schizophrenia and Bipolar Disorder in a Tunisian Population.Biochemical genetics · 2024Article
- The Toll-like Receptor 4 Polymorphism Asp299Gly Is Associated with an Increased Risk of Ovarian Cancer.Cells · 2022Article
- Article
- Lys694Arg polymorphism leads to blunted responses to LPS by interfering TLR4 with recruitment of MyD88.Innate immunity · 2021Article
- Association of TLR4 gene polymorphisms with sepsis after a burn injury: findings of the functional role of rs2737190 SNP.Genes and immunity · 2021Article
- Recent Advances in Biomarkers and Regenerative Medicine for Diabetic Neuropathy.International journal of molecular sciences · 2021Review
- Gene Polymorphisms ofGenes · 2020Article
- Article
- Article
- Unveiling Interindividual Variability of Human Fibroblast Innate Immune Response Using Robust Cell-Based Protocols.Frontiers in immunology · 2020Article
- Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein 180L Single-Nucleotide Polymorphism Is Associated With Susceptibility to Recurrent Pneumococcal Lower Respiratory Tract Infections in Children.Frontiers in immunology · 2018Article
- House Dust Endotoxin and Peripheral Leukocyte Counts: Results from Two Large Epidemiologic Studies.Environmental health perspectives · 2017Article
- Association of Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile with the risk of primary open angle glaucoma.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2017Article
- House Dust Endotoxin Levels Are Associated with Adult Asthma in a U.S. Farming Population.Annals of the American Thoracic Society · 2017Article
- Promoter Polymorphism of Toll-Like Receptor 4 is Associated with a Decreased Risk of Coronary Artery Disease: A Case-Control Study in the Chinese Han Population.Medical science monitor : international medical journal of experimental and clinical research · 2017Article
- Cervical Carcinogenesis and Immune Response Gene Polymorphisms: A Review.Journal of immunology research · 2017Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The common, co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms (SNPs), Asp299Gly and Thr399Ile, are associated with hyporesponsiveness to inhaled lipopolysaccharide (LPS) and increased susceptibility to Gram negative pathogens in humans. The purpose of this study was to identify the relative contributions of the Asp299Gly and the Thr399Ile variants in inhibiting the function of TLR4. 293/hMD2-CD14 cell line was transfected with lentiviral constructs containing human wild type (WT) TLR4-EGFP or TLR4-EGFP with Asp299Gly, Thr399Ile or Asp299Gly/Thr399Ile complementary DNA (cDNA). Multiple stable cell lines were established for each construct: three for WT TLR4, Asp299Gly, and Thr399Ile, and only two for Asp299Gly/Thr399Ile mutants and EGFP control. We did not observe a significant effect of polymorphisms on cell surface and intracellular TLR4 expression nor were there any significant differences in TLR4 and EGFP protein levels assessed by Western blotting and confocal microscopy among the multiple cell lines of each of the constructs. All cell lines had a dose-dependent responsiveness to LPS stimulation. However, compared to the WT TLR4, cells expressing TLR4 with Asp299Gly but not Thr399Ile polymorphism produced significantly less (P<0.05) IL-8 following LPS stimulation. Similarly, cells expressing TLR4 Asp299Gly but not Thr399Ile allele had significantly lower percentage of phosphorylated and total NF-κB P65 following LPS stimulation. While we could not do statistics on the Asp299Gly/Thr399Ile group, we observed a reduced responsiveness to LPS compared to WT TLR4. Taken together, we observed that the TLR4 Asp299Gly variant, but not the Thr399Ile variant, is responsible for impaired responsiveness of TLR4 to LPS and corresponding activation of NF-κB.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.