Toll-like receptor (TLR)-9 promotor polymorphisms and atherosclerosis

Hamann, Lutz; Glaeser, C.; Hamprecht, Axel; Groß, Michael; Gomma, Abuzeid; Schumann, Ralf R.

doi:10.1016/j.cca.2005.07.017

Cited by 65 publications

(47 citation statements)

References 20 publications

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“…26 , 38 , 48 , 49 These exaggerated responses may involve several mechanisms, including changes in ligand binding sites on the receptor, thereby affecting ligand affinity and strength of stimulation, changes in transcription factor binding sites on the TLR promoter, 50 or qualitative/ quantitative changes in the TLR protein. In regard to TLR9 SNP genotypes, the C allele at −1237, in the promoter region, has been shown to affect promoter activity, 51 most likely by modifying a potential binding site for the transcription factor NF-κB.…”

Section: Discussionmentioning

confidence: 99%

“…In regard to TLR9 SNP genotypes, the C allele at −1237, in the promoter region, has been shown to affect promoter activity, 51 most likely by modifying a potential binding site for the transcription factor NF-κB. 50 NF-κB is a complex of proteins that remains in cells in an inactive state and is rapidly activated by a series of cascade events after ligands are bound to TLRs. Qualitative or quantitative changes in NF-κB activation may in turn lead to altered transcription regulation of inflammatory cytokine genes, which could lead to alterations in the production of cytokines such as IFN-γ.…”

Section: Discussionmentioning

confidence: 99%

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TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

Sam-Agudu

Greene

Opoka

et al. 2010

The American Journal of Tropical Medicine and Hygiene

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Abstract. Toll-like receptor (TLR) polymorphisms have been associated with disease severity in malaria infection, but mechanisms for this association have not been characterized. The TLR2, 4, and 9 single nucleotide polymorphism (SNP) frequencies and serum interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were assessed in Ugandan children with cerebral malaria (CM, N = 65) and uncomplicated malaria (UM, N = 52). The TLR9 C allele at −1237 and G allele at 1174 were strongly linked, and among children with CM, those with the C allele at −1237 or the G allele at 1174 had higher levels of IFN-γ than those without these alleles ( P = 0.03 and 0.008, respectively). The TLR9 SNPs were not associated with altered IFN-γ levels in children with UM or altered TNF-α levels in either group. We present the first human data that TLR SNPs are associated with altered cytokine production in parasitic infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

Sam-Agudu

Greene

Opoka

et al. 2010

The American Journal of Tropical Medicine and Hygiene

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“…Deletions spanning the À3.2 to À0.7 kb promoter region did not alter the TLR9 promoter activity, 30 although the region was shown to be important for the Human Papillomavirus 16-mediated inhibition of TLR9 expression. 31 In silico analysis of the TLR9 promoter showed that the À1237T4C change introduces a putative c-Rel/NF-kB transcription factor binding site; 32 in vitro gene reporter assays showed that the TLR9 À1237T4C SNP alters the TLR9 promoter activity, with the À1237T allele having a higher promoter activity (P¼0.018), suggesting the existence of regulatory elements across the polymorphic site 33 and implying that the À1237C allele is associated with lower TLR9 expression levels.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms and haplotypes in TLR9 and MYD88 are associated with the development of Hodgkin's lymphoma: a candidate–gene association study

et al. 2009

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Toll-like receptors (TLRs) and myeloid differentiation primary response protein 88 (MYD88) gene polymorphisms may be involved in the pathogenesis of Hodgkin's lymphoma (HL) through altered immunoregulatory and inflammatory responses. A candidate-gene association study was conducted to investigate the association between TLR9 À1237T4C, TLR9 2848A4G, MYD88 À938C4A and MYD88 1944C4G gene polymorphisms and the risk for HL. The impact of haplotypes was also examined. The study showed that carriership for À1237C and 2848A was associated with an increased risk for HL (odds ratio (OR)¼2.53 (1.36-4.71) and OR¼6.20 (1.3-28.8)). The MYD88 polymorphisms produced nonsignificant results. The estimated frequencies of the TLR9/1237C-2848A and MYD88/938C-1944G haplotypes were also significantly different between HL and controls (Po0.01). In addition, a significant difference between HL and controls was observed for the TLR9/1237C-TLR9/ 2848A-MYD88/938C-MYD88/1944C haplotypes (Po0.01). In conclusion, our study showed that TLR polymorphisms, and TLR9 and MYD88 haplotypes are related to the development of HL.

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“…1). This extra binding site was postulated to enhance the transcriptional activation of TLR9 and potentially affect CpG-DNA-induced activation of proinflammatory chemokines, cytokines, and the adaptive immune response (13). However, a recent report ex-amining the association of rs5743836 with atopic eczema showed that the risk allele was the "T" allele.…”

mentioning

confidence: 99%

Increase in NF-κB Binding Affinity of the Variant C Allele of the Toll-Like Receptor 9 −1237T/C Polymorphism Is Associated with Helicobacter pylori -Induced Gastric Disease

Hof

Crockett

et al. 2010

Infect Immun

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Colonization of the gastric mucosa by Helicobacter pylori can lead to serious clinical outcomes, including gastric cancer. Toll-like receptors (TLRs) play an important role in the host response to H. pylori through the recognition of pathogen-associated molecular patterns. TLR9, in particular, is partly responsible for initiating bacterial induced immunity by binding unmethylated CpG-DNA, which is abundant in bacteria. A welldocumented single nucleotide polymorphism (SNP) within the TLR9 promoter (TLR9 ؊1237T/C), is associated with a variety of inflammatory disorders, including allergic asthma, inflammatory bowel disease, and atopy. Analysis of the TLR9 promoter gene sequence has shown that carriage of the variant "C" allele at position ؊1237 creates a potential NF-B binding site that would theoretically increase the transcriptional activity of the gene. In this study, we report that the TLR9 ؊1237 C allele was significantly associated with the development of H. pylori-induced premalignant gastric changes. Functional analysis of the SNP, supporting the data generated from the genetic association study, showed that carriage of the C allele increased TLR9 transcriptional activity driven mainly by activation of NF-B. Collectively, these findings confirm that the TLR9 ؊1237T/C polymorphism is a risk factor for the development of H. pylori-induced premalignant gastric changes and provide a plausible mechanistic explanation.

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Toll-like receptor (TLR)-9 promotor polymorphisms and atherosclerosis

Cited by 65 publications

References 20 publications

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

Polymorphisms and haplotypes in TLR9 and MYD88 are associated with the development of Hodgkin's lymphoma: a candidate–gene association study

Increase in NF-κB Binding Affinity of the Variant C Allele of the Toll-Like Receptor 9 −1237T/C Polymorphism Is Associated with Helicobacter pylori -Induced Gastric Disease

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