Very Low Frequencies of Toll-Like Receptor 2 Supposed-2029T and 2258A (RS5743708) Mutant Alleles in Southern Brazilian Critically Ill Patients: Would It Be a Lack of Worldwide-Accepted Clinical Applications of Toll-Like Receptor 2 Variants?

Thurow, Helena Strelow; Sarturi, Cladinara Roberts; Fallavena, Paulo Roberto Vargas; Paludo, Francis Jackson de Oliveira; Picanço, Juliane Bentes; Fraga, Lucas Rosa; Graebin, Pietra; Souza, Vinícius Carolino; Dias, Fernando Suparregui; Nóbrega, Otávio de Tolêdo; Alho, Clarice Sampaio

doi:10.1089/gtmb.2009.0169

Cited by 4 publications

(10 citation statements)

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“…According to the SNP database (dbSNP), these genotypes were not found in the 11 HapMap populations (phase 3), which includes the Europeans (CEU). In fact, the A allele (c.2259A>G) is rare – 0.052 in CEU – and was only detected in homozygosity in tuberculosis patients [16]; the T allele (c.2029C>T) is observed in Asian and African populations, but it seems to be absent in white populations [17,18]. Nevertheless, in the present work, the T allele was identified in heterozygosity in one individual, as illustrated in Figure 1C (c.2029C>T) and was confirmed by sequencing (Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

Three multiplex snapshot assays for SNP genotyping in candidate innate immune genes

et al. 2013

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BackgroundInnate immune system is the first line of research when studying immune response to diverse infections and autoimmune/inflammatory diseases. This immune response has been reported to be genetically diverse, due to polymorphisms coded by different genes. For this reason, our purpose was to develop a multiplex assay that allows the genotyping of candidate single nucleotide polymorphisms (SNPs) in innate immune genes.FindingsWe developed three multiplex PCR panels coupled with the minisequencing (SNaPshot) technique (multiplex PCR, multiplex primer extension, and capillary electrophoresis). The panels were tested in a sample set composed of 100 anonymous DNAs from healthy blood donors living in São Miguel Island (Azores, Portugal). Sixteen relevant SNPs among nine genes of the innate immune system – IL1α, IL1β, IL6, IL10, IL12RB1, TLR2, TLR4, TLR9 and CD14 – were genotyped and validated by direct sequencing, with the exception of one that was undetected by minisequencing. We suggest that these panels can be used in future studies for detection of risk gene variants in several populations and/or diseases.ConclusionsIn summary, we propose a multiplex assay that is able to identify the most frequent candidate SNPs in innate immune genes, using a medium scale genotyping platform. The assays can be used to evaluate the risk gene variants in populations of various geographic origins.

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Section: Resultsmentioning

confidence: 99%

Three multiplex snapshot assays for SNP genotyping in candidate innate immune genes

et al. 2013

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“…Genomic DNA was extracted from leucocytes by a standard method . The ‐260C>T CD14 (rs2569190; NT_029289.11:g.1175843A>G), 2029C>T TLR2 (no rs number) and 2258G>A (rs5743708; p.Arg753Gln; NT_016354.19:g.79174038G>A) TLR2 genotyping was performed as previously described . TNF‐α ‐308G>A SNP (rs1800629; NT_007592.15:g.31483031G>A) and TLR4 896A>G and 1196C>T SNPs (rs4986790; p.Asp299Gly; g.13843A>G) and 1196C>T (rs4986791; p.Thr399Ile; g.14143C>T), based on Arbour et al .…”

Section: Methodsmentioning

confidence: 99%

The Synergy of ‐260T T CD14 and ‐308GG TNF‐α Genotypes in Survival of Critically Ill Patients

et al. 2012

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Literature suggests that the analysis of several polymorphic genetic markers is more informative than the analysis of a single polymorphism. In this study, we tested whether the shared inheritance of TLR2 and TLR4 and TNF-a allelic variants may act in synergy with -260C>T CD14 SNP on the outcome from critical conditions. We monitored 524 critically ill patients from South Brazilian, daily from the ICU admission to their discharge from hospital, or death. Our results revealed that TLR2, TLR4 or TNF-a SNPs alone did not show a significant role in the outcome from critical illness. However, when we performed a combined analysis with the CD14 inheritance, we detected a significant higher survivor rate in -260TT CD14/-308GG TNF-a individuals (P = 0.037). In the adjusted analysis including the main clinical predictors to mortality, we observed that -260TT/-308GG double-genotype was a significant protective factor towards survival (P = 0.046). An increased probability for survival of -260TT/-308GG was also observed by 'pathway genetic load' analysis (unweighted: P = 0.041; weighted: P = 0.036). When we applied a hazard function analysis with the -260TT/-308GG variable as a discriminating factor, -260TT/-308GG patients group had, in fact, a higher survivor rate (P = 0.024). Connected to the beneficial effect of -260TT CD14, the -308GG TNF-a genotype was protective against the reported over expression of TNF-a caused by -308A rare allele. Results support the hypothesis that the interaction between -260C>T CD14 and -308G>A TNF-a functional SNPs may be synergistically influencing the outcome of critically ill patients.

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“…Some researches have shown that innate and adaptive immune responses have a particularly important relationship with gene regulation. [3][4][5][6][7][8] Toll-like receptors (TLRs) play an important role in innate immune responses. It can activate inflammatory signal transduction pathway by identifying pathogenic molecules and binding to the corresponding receptors.…”

Section: Introductionmentioning

confidence: 99%

“…It can activate inflammatory signal transduction pathway by identifying pathogenic molecules and binding to the corresponding receptors. [3,4] TLR4, a member of TLR family, is an important lipopolysaccharide (LPS) ligand which participate in the generation of inflammatory factors. [3,4] Single nucleotide polymorphisms (SNPs) are present in TLR4.…”

Section: Introductionmentioning

confidence: 99%

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Expression of toll-like receptor 4 gene polymorphism and inflammatory factors in peripheral blood on patients with sepsis

Tian¹,

Xu²,

Yang³

2021

DCC

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Objective: To observe the presence of toll-like receptor 4 (TLR4) gene polymorphism in the venous blood in patients with sepsis, meanwhile, to observe the expression and the diagnostic value of TLR4 mRNA, interferon-γ (IFN-γ), interleukin-23 (IL-23), procalcitonin (PCT) and C-reactive protein (CRP) in patients with different degrees of sepsis.Methods: The peripheral blood samples from the subjects were collected to extract genomic DNA, gene sequencing and enzyme digestion method were applied to the detection of TLR4 Asp299Gly loci polymorphism. The expression of TLR4 mRNA in the peripheral blood was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The expression levels of IFN-γ, IL-23, PCT and CRP were measured by enzyme linked immunosorbent assay (ELISA).Results: (1) The gene polymorphism was not present in TLR4 Asp299Gly loci; (2) The expression of TLR4 mRNA in the peripheral blood in patients with sepsis: on d1, there were statistically significant differences between the normal group and the group (APACHE II ≤ 20), between the normal group and the group (APACHE II > 20), between the group (APACHE II ≤ 20) and the group (AAPACHE II > 20) (t = 5.741, 14.780 and 10.500, all p < .01). APACHE II stands for Acute Physiology and Chronic Health Evaluation II. On d7, there were statistically significant differences between the normal group and the group (APACHE II ≤ 20), between the normal group and the group (APACHE II > 20), between the group (APACHE II ≤ 20) and the group (APACHE II > 20) (t = 4.186, 13.830 and 9.645, all p < .01); (3) The expression levels of IFN-γ, IL-23, PCT and CRP were obviously upregulated (all p < .01), and TLR4 was positively correlated with IFN-γ and IL-23 (all p < .01); (4) The best cutoff value of TLR4 mRNA at baseline was 891.6 μg/L, with a sensitivity of 100% and a diagnostic specificity of 57%. The best cutoff value of IFN-γ at baseline was 84.5 μg/L, with a sensitivity of 100% and a diagnostic specificity of 57%. The best cutoff value of IL-23 at baseline was 861 μg/L, with a sensitivity of 100% and a diagnostic specificity of 97%.Conclusions: (1) The Asp299Gly polymorphism is not present in TLR4 gene; (2) The expression levels of TLR4 mRNA, IFN-γ and IL-23 are relatively high in patients with sepsis, and will be higher with the increased severity of sepsis; (3) TLR4 mRNA, IFN-γ and IL-23 can be used as molecular biomarkers for the early diagnosis of sepsis.

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Very Low Frequencies of Toll-Like Receptor 2 Supposed-2029T and 2258A (RS5743708) Mutant Alleles in Southern Brazilian Critically Ill Patients: Would It Be a Lack of Worldwide-Accepted Clinical Applications of Toll-Like Receptor 2 Variants?

Cited by 4 publications

References 55 publications

Three multiplex snapshot assays for SNP genotyping in candidate innate immune genes

Three multiplex snapshot assays for SNP genotyping in candidate innate immune genes

The Synergy of ‐260T T CD14 and ‐308GG TNF‐α Genotypes in Survival of Critically Ill Patients

Expression of toll-like receptor 4 gene polymorphism and inflammatory factors in peripheral blood on patients with sepsis

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