Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms: New data and a meta-analysis

Abstract

BackgroundThe pathogenesis of inflammatory bowel disease (IBD) involves interactions between the host genetic susceptibility, intestinal microflora and mucosal immune responses through the pattern recognition receptor. Polymorphisms in toll-like receptor 4 (TLR4) induce an aberrant immune response to indigenous intestinal flora, which might favor IBD development. In this study, we aimed to determine whether TLR4 gene was associated with Crohn’s disease (CD) and ulcerative colitis (UC) among Moroccan patients, and evaluated its correlation with clinical manifestation of the disease.MethodsThe study population comprised 117 patients with IBD and 112 healthy unrelated blood donors. TLR4 polymorphisms: Asp299Gly and Thr399Ile were genotyped by polymerase chain reaction-restriction fragment length polymorphism. PCR products were cleaved with Nco I for the Asp299Gly polymorphism and Hinf I for the Thr399Ile polymorphism. Meta-analysis was performed to test the association of 299Gly and 399Ileu carriage with CD, UC and the overall IBD risk.ResultsOur study revealed that the frequency of Asp299Gly and Thr399Ile did not differ significantly between patients and controls in the Moroccan population. However, meta-analysis demonstrated significantly higher frequencies of both Asp299Gly and Thr399Ile SNPs in IBD and CD and for 399Ileu carriage in UC patients.ConclusionThe meta-analysis provides evidence that TLR4 polymorphisms confer a significant increased risk for the overall IBD development.

Expression of Toll-like receptor (TLR) 2 and TLR4 in the livers of mice infected by Clonorchis sinensis

“…Once PAMPs are recognized by leucine-rich domains, the signal cascades are initiated, and remarkable proinflammatory cytokines and chemokines, as well as costimulatory molecules, are ultimately induced through the activation of a variety of transcriptional complexes including NF-κB and AP-1 [11][12][13][14][15]. Additionally, host susceptibility to infectious diseases may be associated with the TLRs' polymorphisms [16][17][18].…”

Genetic association and phenotypic correlation of TLR4 but not NOD2 variants with Tunisian inflammatory bowel disease

“…Cheng et al have also reported that this TLR4 polymorphism is associated with susceptibility to IBD in Caucasians . However, a previous Tunisian study failed to find any association between the allelic and genotypic TLR4 T399I polymorphism and disease susceptibility, which was replicated in another North African study including Moroccan patients with IBD . In the Tunisian population the heterogeneity in findings could be explained by the difference in patient recruitment.…”

“…TLR4 is involved in the recognition of bacterial lipopolysaccharides and in triggering innate immune responses . Two missense polymorphisms (Asp299Gly and Thr399Ile) of TLR4 gene affecting the extracellular domains of the molecule seem to cause lipopolysaccharide hypo‐responsiveness and susceptibility to develop intestinal inflammation …”

Association between Toll-Like Receptor 4 T399I Gene Polymorphism and the Susceptibility to Crohn’s Disease: A Meta-Analysis of Case-Control Studies

“…After the assessment of eligibility using full-text, 22 articles were excluded. Finally, 15 articles met all inclusion criteria and were included in the meta-analysis [16-20, 27-36]. Selected details of the individual studies are listed in Table 1.…”

“…Through a combination of all the available published data, it is hypothesized that a meta-analysis with increased statistical power might allow causative genes to be identified and plausible candidate genes to be excluded with reliability. Although there have been some meta-analyses focus on TLR4 polymorphism and CD, the relationship between TLR4 T399I gene polymorphism and the susceptibility to CD is controversial [20, 21]. Therefore, we conducted the present meta-analysis to quantitatively assess this relationship.…”