Genetic Polymorphisms In Toll-like Receptor Research Articles

Prediction of uncontrolled course of bronchial asthma in children based on polymorphisms of genes of signaling molecules of the immune system and detoxification genes

Aim. To study the possibility of predicting the asthma control at various stages of the development of the disease, possibly on the basis of taking into account the genetic polymorphisms of Toll-like receptors, cytokines and detoxification system genes using the statistical method of learning neural networks.Materials and methods. We ex­amined 167 children with bronchial asthma. The degree of asthma control was determined, the following mutations were detected: TLR2-Arg753Glu, TLR4-Asp299Gly, TLR4-Ghr399Ile, TLR9-T1237C, TLR9-A2848G; IL4-C589T, IL6- C174G, IL10-G1082A, IL10-C592A, IL10-C819T, IL12B-A1188C, TNFa-G308A; GSTM, GSTT, GSTM/GSTT, GSTP1 Ile105Val, GSTP1 Ala114Val, by PCR. The STATISTICA Automated Neural Networks package was used to model neural networks.Results. The model is based on the MLP (15-9-3) multilayer perceptron architecture with a layer of 15 input neurons (by the number of analyzed variables), a hidden intermediate layer of 9 neurons and an output layer of 3 neurons by the number of values of the classified variable (control). The training algorithm was chosen by BFGS as the most adequate to the classification task. The error function is traditionally chosen as the sum of squared deviations. The activation function of output neurons is Softmax. The activation function of the intermediate layer is hyperbolic. The volume of the training sample was 88 sets. The volume of samples for testing and quality control of the model was 36 sets. The resulting model was able to predict 79.01% of the correct values of the target variable (the degree of asthma control).Conclusion. The application of the developed program makes it possible to predict the possibility of uncontrolled or partially controlled asthma at any stage of the disease, including preclinical and pre-nosological for groups with a high risk of asthma. This allows you to individually adjust the measures of secondary and even primary prevention of asthma within the personal­ization of therapeutic approaches.

Genetic polymorphisms of toll-like receptors in leprosy patients from southern Brazil.

Leprosy is a chronic disease and also a global health issue, with a high number of new cases per year. Toll-like receptors can respond to mycobacterial molecules in the early stage of infection. As important components of the innate immune response, alterations in genes coding for these receptors may contribute to susceptibility/protection against diseases. In this context, we used a case-control study model (183 leprosy cases vs. 185 controls) to investigate whether leprosy patients and the control group, in southern Brazil, have different frequencies in TLR1 (TLR1 G>T; rs5743618), TLR2 (TLR2 T>C, rs1816702 and rs4696483), and TLR4 (TLR4 A>G, rs1927911) polymorphisms. Analysis of the TLR1 1805G>T polymorphism presented the G/G genotype more frequently in the control group. TLR2 T>C rs1816702 and TLR2 T>C rs4696483, the T/T and C/T genotype, respectively, were more frequent in the control group than in leprosy patients, suggesting protection from leprosy when the T allele is present (rs4696483). Haplotype analyses between TLR1 (rs5743618) and TLR2 (rs1816702 and rs4696483) polymorphisms suggest risk for the presence of the TCC haplotype and protection in the presence of the TCT haplotype. This study suggests that polymorphisms in TLR1 and TLR2 are factors that may contribute to development/resistance of leprosy.

Toll-Like Receptor Signalling Pathways and the Pathogenesis of Retinal Diseases.

There is growing evidence that the pathogenesis of retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) have a significant chronic inflammatory component. A vital part of the inflammatory cascade is through the activation of pattern recognition receptors (PRR) such as toll-like receptors (TLR). Here, we reviewed the past and current literature to ascertain the cumulative knowledge regarding the effect of TLRs on the development and progression of retinal diseases. There is burgeoning research demonstrating the relationship between TLRs and risk of developing retinal diseases, utilising a range of relevant disease models and a few large clinical investigations. The literature confirms that TLRs are involved in the development and progression of retinal diseases such as DR, AMD, and ischaemic retinopathy. Genetic polymorphisms in TLRs appear to contribute to the risk of developing AMD and DR. However, there are some inconsistencies in the published reports which require further elucidation. The evidence regarding TLR associations in retinal dystrophies including retinitis pigmentosa is limited. Based on the current evidence relating to the role of TLRs, combining anti-VEGF therapies with TLR inhibition may provide a longer-lasting treatment in some retinal vascular diseases.

Associations Among Disseminated Intravascular Coagulation, Thrombocytopenia Cytokines/Chemokines and Genetic Polymorphisms of Toll-Like Receptor 2/4 in Chinese Patients with Sepsis.

Objectives(s)Toll-like receptors (TLRs) on platelets have been extensively studied. Both TLR2 and TLR4 have been shown to augment platelet activation and alter its function from a hemostatic regulator to an immune sentinel. However, few studies have investigated the relationship between genetic polymorphisms in TLR2, TLR4 and platelets. We investigated whether genetic polymorphisms of TLR2 and TLR4 were related to thrombocytopenia and coagulation failure in Chinese patients with sepsis.Basic MethodsAdult Chinese patients with sepsis in the intensive care unit of a university medical center were monitored for up to 28 days. Thrombocytopenia and disseminated intravascular coagulation (DIC), diagnosed using Japanese Association for Acute Medicine (JAAM) criteria, were observed as the primary outcomes. Single-nucleotide polymorphisms (SNPs) in TLR2 (rs111200466, rs5743708) and TLR4 (rs11536889, rs145801336, rs11536896, rs7869402) in patients with sepsis were detected by polymerase chain reaction. The data were analyzed using chi-square and rank sum tests.ResultsThe genotype of TLR2 (rs111200466) (Del/Del) was associated with the initial DIC. The genotype of TLR4 (rs11536889) (C/C&C/G) was associated with initial DIC, DIC onset during hospitalization and platelet counts. Furthermore, both DIC and platelet counts were associated with cytokines and chemokines, especially the IL10.ConclusionOur results demonstrate that in Chinese sepsis patients, the rs111200466 SNP in TLR2 and rs11536889 SNP in TLR4 are associated with thrombocytopenia and DIC, with potential effects on the TLR4 pathways of platelets.

Genetic variants in the regulation region of TLR4 reduce the gastric cancer susceptibility.

Gastric cancer (GC) is one of the most common cancers diagnosed in China. It has been suggested that the genetic polymorphisms of Toll-like receptors (TLRs) might be in close relation to tumorigenesis and development of gastric cancer. In this study, we performed a case-control study to investigate the genetic polymorphisms of TLR3, 4, 5, 7 with the genetic susceptibility of gastric cancer. TLRs gene polymorphisms in 471 gastric cancer (GC) patients and 471 healthy controls were analyzed by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis or TaqMan assays. Odds ratio (OR) and its 95% confidence interval (95%CI) were used to evaluate the association of TLR4 variants with the GC risk via unconditional logistic regression. Our results suggested that variant genotypes of TLR4 rs7869402 (OR=0.61, 95%CI=0.40-0.92, P=0.02) and TLR4 rs7873784 (OR=0.17, 95%CI=0.09-0.33, P<0.01) gene polymorphisms reduced the risk of GC. Stratified analysis showed that rs7869402 T-containing genotype significantly decreased the susceptibility of GC among females (OR=0.38, 95%CI=0.16-0.91, P=0.03), older subjects (OR=0.48, 95%CI=0.26-0.87, P=0.02), non-smokers (OR=0.41, 95%CI=0.23-0.71, P<0.01) and non-drinkers (OR=0.58, 95%CI=0.30-0.78, P<0.01). In case of rs7873784 polymorphism, C-containing genotype reduced the risk of GC among males (OR=0.08, 95%CI=0.03-0.21, P<0.01), but not among females (OR=0.53, 95%CI=0.22-1.27, P=0.15). As to the other four SNPs (TLR3 rs5743303, TLR4 rs1927914, TLR5 rs1640816 and TLR7 rs3853839), no significant correlations were found to be related to the risk of gastric carcinoma. Our research demonstrated the significance of TLRs polymorphisms in decreasing the risk of GC.

THE ASSOCIATION BETWEEN GENETIC POLYMORPHISMS OF TOLL-LIKE RECEPTORS AND MANNOSE-BINDING LECTIN AND ACTIVE TUBERCULOSIS IN HIV-INFECTED PATIENTS

Objectives: to analyze the association between genetic polymorphisms of Toll-like receptors (TLR) and mannose-binding lectin (MBL) and active tuberculosis in HIV-infected patients to consider the possibility of using genetic markers as a way to personalize the chemoprophylaxis of tuberculosis in this category of patients. Materials and methods : The study enrolled 171 patients (85 HIV-infected, 86 HIV/TB co-infected patients). Single nucleotide polymorphisms (SNP) in the TLR4 (rs4986790), TLR2 (rs5743708) and MBL2 (rs5030737, rs1800450, rs1800451) were genotyped by real-time PCR and pyrosequencing. Data about epidemiological risk factors were obtained from epidemiological anamnesis. Immune status was assessed by the level of CD4+ T-cells count. Results : Statistically significant association with active tuberculosis was identified for the genotype AG of TLR4, rs4986790 (OR=5.2; 95% CI: 1,8–14,6, p=0,002). Multivariate analysis shows that close contact with TB patientand status of ex-prisoner increased the risk of active tuberculosis 5,2 times (OR=5,2; 95% CI: 1,4–18,5, p=0,012 and OR=5,2; 95% CI: 1,5–17,7, p=0,009, respectively); CD4+ T-cell count more than 200 cells/mm 3 exerted protective effect and reduced the risk of developing TB 5 times (OR=0,2; 95% CI: 0,1–0,5, p=0,001). The genotype AG of TLR4, rs4986790 increased the risk of active tuberculosis 3,7 times (OR=3,7; 95% CI: 1,1–13,1, p=0,046). Conclusion . The G allele of TLR4, rs4986790 can be considered as an independent risk factor for active tuberculosis in HIV-infected individuals. These results need to be confirmed by further investigations on large samples.

Genetic Polymorphisms of Toll-like receptors 2 and 9 as Susceptibility Factors for the Development of Ankylosing Spondylitis and Psoriatic Arthritis.

Introduction Ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are classified as spondyloarthritis (SpA), a group of inflammatory rheumatic diseases with complex genetic etiology. Toll-like receptors (TLRs) have an important role in the mechanism of innate immunity and may influence inflammatory responses. Polymorphisms in TLR genes that lead to changes in these receptors or that interfere with the transcription rates of mRNA TLR may be involved in the chronic inflammatory immune response observed in SpA. Currently, there is a lack of studies associating genetic polymorphisms in TLRs and SpA. Objective Therefore, this case-control study is aimed at analyzing the influence of the respective SNPs on TLR2 rs5743708, TLR6 rs5743810, and TLR9 rs5743836 and rs187084 in the immunopathogenesis of SpA. Methods The polymorphisms genotyped by PCR-RFLP were TLR2 rs5743708, TLR6 rs5743810, and TLR9 rs5743836 and rs187084. The HLA-B∗27 was performed by PCR-SSP. Results Logistic regression analysis showed a strong association between SNPs in TLR2 and TLR9 and susceptibility to SpA (OR = 12.56; CI = 6.5-25.9 and OR = 1.62; CI = 1.20-2.21, respectively). No association was observed among HLA-B∗27 and TLR polymorphisms (p = 0.72), nor among BASDAI and TLR polymorphisms (p = 0.85). Discussion Our findings suggest that polymorphisms in TLR2 and TLR9 genes may contribute to the immunopathogenesis of the SpA. The rs187084, rs5743836, and rs5743708 polymorphisms were associated with the risk of SpA development, in this study, and lead to significant changes in the innate and adaptive immune response profile, as well as the maintenance of the regulation of immunological mechanisms. Conclusion The polymorphism rs5743708 for the TLR2 and the rs187084_rs5743836 TLR9 haplotypes appear to be involved in the development of clinical forms of SpA and can be a possible therapeutic target for the spondyloarthritis.

Impact of Toll-like Receptors 2(TLR2) and TLR 4 Gene Variations on HCV Susceptibility, Response to Treatment and Development of Hepatocellular Carcinoma in Cirrhotic HCV Patients

ABSTRACTBackground and Aims: Genetic polymorphisms of Toll-like receptors (TLRs) have been proposed to affect susceptibility to HCV infection and progression to end-stage liver disease. This study was conducted to clarify the association of SNPS of TLR2 and TLR4 with clinical outcome of hepatitis C, response to treatment and development of HCC.Methods: The current study examined 3295 individuals from 725 families that were categorized into groups comprising chronic HCV (CH), spontaneous viral clearance (SC) and control subjects. Treated patients were classified into responders (RT) and non-responders (NRT). In addition, patients with liver cirrhotic (LC), and hepatocellular carcinoma (HCC) were also included. All subjects were genotyped for five single nucleotide polymorphisms (SNPs) of TLR2 and four SNPs of TLR4 and their haplotypes using allelic discrimination real-time PCR.Results: Results demonstrated strong association with allele A of rs13105517 of TLR2 and allele C of rs10116253 of TLR4 with CH in comparison to SC group. However, The peak of risk of HCC was observed with allele C of rs3804099 of TLR2 and C allele of rs10116253 TLR4 (p < 0.001).A strong association was found with allele T of rs1816702 of TLR2 and allele A of rs5030728 of TLR4 in non responder group in comparison to responders (p < 0.001). Haplotypes CAGT of TLR4 and ATAC of TLR2 showed significant association with CH and HCC groups in comparison to other groups.Conclusions: This study shows an association of minor alleles of TLR2 and TLR4 with outcome of HCV infection, response to therapy and development of HCC in cirrhotic patients.

Genetic polymorphisms in toll-like receptors 1, 2, and 4 in feline upper respiratory tract aspergillosis

Fungal species in the genus Aspergillus are environmental saprophytes that can act as opportunistic pathogens of the nasal cavity and paranasal sinuses in humans, cats and other species. Upper respiratory tract aspergillosis (URTA) presents as non-invasive and invasive forms with the latter occurring almost exclusively in immunocompromised hosts. However, in domestic cats, invasive URTA affects apparently immunocompetent patients. A defect in innate immunity has been proposed as a predisposing factor in invasive feline URTA. Single nucleotide polymorphisms (SNPs) in pattern recognition receptor genes have been implicated in the pathogenesis of aspergillosis in humans. The aims of this study were to identify non-synonymous SNPs in the coding regions of toll-like receptors involved in the immune response to Aspergillus spp. and to compare the frequency of these SNPs between affected and control cats. The coding and flanking regions of TLR1, TLR2 and TLR4 were sequenced in 14 cats with URTA and the sequences were compared with those in 20 control cats without aspergillosis. In total, 23 non-synonymous SNPs were identified in TLR1 (n = 11), TLR2 (n = 3) and TLR4 (n = 10). Differences in allelic frequency of non-synonymous SNPs between affected and controls were not identified either within breeds or overall or between non-invasive and invasive disease phenotypes. Although allelic frequency differed between cat breeds that are overrepresented for URTA and underrepresented breeds there was no association differences identified between affected cats and underrepresented breeds. The difference in allelic frequency of an INDEL point mutation identified in intron 1 of TLR4, between cats with non-invasive versus invasive aspergillosis approached significance (p = 0.054). While results from this study do not support a role for non-synonymous SNPs in the pathogenesis of feline URTA they do provide evidence that investigation for polymorphisms in non-coding regions of these genes and in other pattern recognition receptors are warranted.

TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer.

Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H. pylori infection, atrophic gastritis (AG) or GC in the European population. Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum. The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26-2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26-2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed. TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

Interaction of H. pylori with toll-like receptor 2-196 to -174 ins/del polymorphism is associated with gastric cancer susceptibility in southern China.

Genetic polymorphisms of Toll-like receptors play important roles in gastric carcinogenesis. The aim of this study was to determine the role of TLR2-196 to -174 ins/del polymorphism in gastric cancer susceptibility and prognosis. This study included 520 people from southern China. Samples were genotyped by the allele-specific polymerase chain reaction, among which 10% were randomly selected for sequencing. The serological method was used to determine Helicobacter pylori. The TLR2 genotype was not associated with the risk of H. pylori infection. The del/del genotype exhibited significantly higher gastric cancer risk (adjusted OR 2.59, 95% CI 1.33‒5.07) than that of the ins/ins genotype. Further stratification analyses demonstrated that the del/del genotype was associated with a risk of intestinal gastric cancer (adjusted OR 2.62, 95% CI 1.34-5.14). In addition, the presence of the del/del genotype and the H. pylori infection conferred a synergistic effect (OR 3.04, 95% CI 1.33‒6.98) for the development of gastric cancer. The del/del genotype was not associated with a poor prognosis in gastric cancer patients. The del/del genotype is associated with an increased gastric cancer risk in the southern Chinese population. However, TLR2 polymorphism is neither associated with H. pylori infection, nor with a poor prognosis.

Toll-like receptor 2 and 4 polymorphisms associated with Helicobacter pylori susceptibility and gastric cancer.

Genetic polymorphisms in Toll-like receptors (TLRs) are important influence on gastric lesion development and Helicobacter pylori susceptibility. TLR2 rs3804099 and rs3804100 and TLR4 rs10759932 were determined in a total of 400 patients. The association among genotypes and the risk of gastric lesion development and H. pylori susceptibility were evaluated by the odds ratios (ORs) and 95% confidence intervals (95% CIs) from logistic regression analyses. TLR4 rs10759932, C/C homozygous genotype was associated with an increased risk of premalignant/malignant (OR=2.48, 95% CI=1.96-4.62, p=0.015). The recessive model of TLR4 rs10759932 showed a decreased risk of H. pylori susceptibility (adjusted OR=0.52, 95% CI=0.38-0.82, p=0.046). Meanwhile, the recessive model was associated with an increased risk of non-malignant (OR=3.46, 95% CI=2.25-5.67, p=0.001). In subjects with H. pylori infection, the recessive model was associated with an increased risk of non-malignant (OR=2.28, 95% CI=1.24-3.57, p=0.001) and premalignant/malignant (OR=1.83, 95% CI=1.16-2.84, p=0.027). TLR4 rs10759932, but not TLR2 rs3804099 and rs3804100, was associated with risk of premalignant and/or malignant and H. pylori susceptibility. H. pylori infection seems to contribute to chronic gastritis, and premalignant/malignant supported the development of the premalignant/malignant lesions involved in H. pylori infection that is critical to gastric cancer in Thai patients.

Polimorfismos genéticos asociados a la inmunidad innata y la susceptibilidad genética a la tuberculosis

Tuberculosis is a global health problem exacerbated by the absence of an effective vaccine and emergence of extensive antibiotic-resistant strains. Innate immunity is key to tuberculosis susceptibility, since it is associated with genetic polymorphisms in TLRs (Toll Like Receptors), VDR (Vitamin D Receptor), INF-γ, TNF-α, among others. Recently, also to nine Mendelian Susceptibility Mycobacterial Diseases (MSMD) -causing genes, including autosomal and X-linked genes. After decades of successful management, Chile reported maintenance of mortality and increase in tuberculosis under 15 years and multidrug resistant cases incidence. Moreover, incidence is higher in the North and the Center, where Metropolitan Region showed a sustained increment of the Latin American migrant population. Consequently, the high incidence persistence in such geographic areas could be associated with populations carrying SNPs genetic polymorphisms types and/or MSMD that confer genetic susceptibility to tuberculosis and/or BCG dissemination and other intramacrophagic pathogens, similar to that described in certain populations in Europe, Asia, Africa and America. Corollary, we propose to consider genetic predisposition of the current population, at the time of designing national public health policies to eradicate tuberculosis.

Association of TLR variants with susceptibility to Plasmodium vivax malaria and parasitemia in the Amazon region of Brazil.

BackgroundPlasmodium vivax malaria (Pv-malaria) is still considered a neglected disease despite an alarming number of individuals being infected annually. Malaria pathogenesis occurs with the onset of the vector-parasite-host interaction through the binding of pathogen-associated molecular patterns (PAMPs) and receptors of innate immunity, such as toll-like receptors (TLRs). The triggering of the signaling cascade produces an elevated inflammatory response. Genetic polymorphisms in TLRs are involved in susceptibility or resistance to infection, and the identification of genes involved with Pv-malaria response is important to elucidate the pathogenesis of the disease and may contribute to the formulation of control and elimination tools.Methodology/Principal findingsA retrospective case-control study was conducted in an intense transmission area of Pv-malaria in the state of Amazonas, Brazil. Genetic polymorphisms (SNPs) in different TLRs, TIRAP, and CD14 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 325 patients infected with P. vivax and 274 healthy individuals without malaria history in the prior 12 months from the same endemic area. Parasite load was determined by qPCR. Simple and multiple logistic/linear regressions were performed to investigate association between the polymorphisms and the occurrence of Pv-malaria and parasitemia. The C/T (TLR5 R392StopCodon) and T/T (TLR9 -1486C/T) genotypes appear to be risk factors for infection by P. vivax (TLR5: C/C vs. C/T [OR: 2.116, 95% CI: 1.054–4.452, p = 0.031]; TLR9: C/C vs. T/T [OR: 1.919, 95% CI: 1.159–3.177, p = 0.010]; respectively). Fever (COEF = 7599.46, 95% CI = 3063.80–12135.12, p = 0.001) and the C/C genotype of TLR9 -1237C/T (COEF = 17006.63, 95% CI = 3472.83–30540.44, p = 0.014) were independently associated with increased parasitemia in patients with Pv-malaria.ConclusionsVariants of TLRs may predispose individuals to infection by P. vivax. The TLR5 R392StopCodon and TLR9 -1486C/T variants are associated with susceptibility to Pv-malaria. Furthermore, the TLR9 variant -1237C/C correlates with high parasitemia.

Genetic polymorphisms in Toll-like receptor 3 gene are associated with the risk of hepatitis B virus-related liver diseases in a Chinese population

Toll-like receptors (TLRs) are well known to play a critical role in antiviral and antitumor response. Available evidence has demonstrated that TLRs are implicated in the immunopathogenesis of hepatitis B virus (HBV) infection and tumor carcinogenesis. Therefore, we performed the present study to investigate the relationship with TLR3 gene polymorphisms and the risk of HBV-related liver disease in a Chinese population. A total of 623 individuals were included: 172 chronic hepatitis B (CHB) patients, 91 HBV-related liver cirrhosis (LC) patients, 174 HBV-related hepatocellular carcinoma (HCC) patients, and 186 healthy controls. Allelic and genotypic frequencies of TLR3 rs1879026 and rs3775290 polymorphisms were detected by PCR-RFLP and DNA sequencing analysis. Association analysis showed that the TT genotype of TLR3 rs3775290 was associated with a decreased risk for CHB, HBV-related LC, and HCC (OR=0.52, 95% CI: 0.27–0.99, P=0.048; OR=0.32, 95% CI: 0.14–0.76, P=0.010; OR=0.49, 95% CI: 0.26–0.92, P=0.027). Nevertheless, a lack of association was found between TLR3 rs1879026 and HBV-related liver diseases. In addition, haplotype analysis revealed that individuals who carried the GT haplotype might have a decreased risk of HBV-related liver diseases. The results indicated that genetic variant in TLR3 gene rs3775290 polymorphisms may be a protective factor for CHB, HBV-related LC, and HCC in the Chinese population.

Toll-like receptor 1 and 10 polymorphisms, Helicobacter pylori susceptibility and risk of gastric lesions in a high-risk Chinese population

Genetic polymorphisms of Toll-like receptor (TLR) 1 and 10 may influence Helicobacter pylori (H. pylori) susceptibility. To evaluate associations between TLR1 and 10 polymorphisms, H. pylori infection, and precancerous gastric lesions, a population-based study was conducted in a high-risk Chinese population.Three single-nucleotide polymorphisms, TLR1 rs4833095, TLR10 rs10004195, and TLR10 rs4129009 were genotyped by TaqMan SNP genotyping assay in 2553 participants with diverse gastric lesions. The status of H. pylori infection was determined by 13C-urea breath test.TLR1 rs4833095 T and TLR10 rs10004195 T alleles were the minor alleles and showed in linkage disequilibrium (D′=0.98, r2=0.73) in the Chinese population. A decreased risk of H. pylori infection was observed in subjects with TLR1 rs4833095 CT genotype [adjusted odds ratio (OR)=0.80; 95% confidence interval (CI): 0.66–0.96] or T allele (OR=0.82; 95%CI: 0.69–0.99). Moreover, subjects carrying TLR1 rs4833095 TT genotype were associated with reduced risks of chronic atrophic gastritis (CAG, OR=0.66; 95%CI: 0.45–0.97) and intestinal metaplasia (IM, OR=0.57; 95%CI: 0.36–0.90). The risk of CAG was also decreased in subjects carrying TLR10 rs10004195 T allele (OR=0.75; 95%CI: 0.57–0.99). Furthermore, haplotype analysis indicated that haplotype TT of rs4833095 and rs10004195 had a protective effect on H. pylori infection (OR=0.83; 95%CI: 0.72–0.96) or precancerous gastric lesions (OR=0.78; 95%CI: 0.64–0.96 for CAG, and OR=0.74; 95%CI: 0.57–0.96 for IM).These findings suggest that TLR1 rs4833095 and TLR10 rs10004195 may play crucial roles in H. pylori susceptibility and gastric pathogenesis.

Genetic Polymorphisms of Toll-like Receptor 4 are Associated with Respiratory Syncytial Virus Infection in a Chinese Infant Population.

While genetic polymorphisms in Toll-like Receptor 4 (TLR4) have been demonstrated to play an important role in respiratory syncytial virus (RSV) infections in Western populations, the association between TLR4 polymorphisms and RSV infections has not been investigated in Chinese patient populations. The study presented here identifies TLR4 polymorphisms and investigates the association of TLR4 genetic polymorphism with RSV infection in a Chinese infant patient population. One-hundred and ninety-six infants hospitalized with RSV infections and 311 healthy control subjects were enrolled in this study. Genetic polymorphisms in the 5' untranslated region (5'UTR), exons, and 3' untranslated region (3'UTR) of the TLR4 gene were screened using PCR and sequencing analysis. The association between the genetic polymorphisms in TLR4, RSV infection risk, and the related disease severity was investigated using Fisher's Exact Test and the Chi-square test. Fourteen different genetic polymorphisms within the TLR4 gene, including two in the 5'UTR, four in the exons, and eight in the 3'UTR were found in the study population. Two polymorphisms, Asp299Gly and Thr399Ile, typically associated with RSV in Caucasian infants were not observed in the Chinese infants. Of the 14 polymorphisms, only rs41426344 (G/C) in the 3'UTR of the TLR4 gene was found to be associated with RSV infection risk and disease severity. The TLR4 genetic polymorphism rs41426344 may be a specific genetic risk factor in Chinese infants associated with RSV infection and disease severity.

Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes

This study aimed to demonstrate possible associations between genetic polymorphisms in Toll-like receptor 3, interferon induced with helicase C domain 1 (IFIH1) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 and systemic lupus erythematosus (SLE), including the phenotypes lupus nephritis and malar rash, as well as the presence of autoantibodies against nucleic acid-containing complexes. Genotyping was carried out in two Danish cohorts [Copenhagen (CPH) and Odense (ODE)] totaling 344 patients and was compared with 641 previously genotyped healthy controls. In the ODE cohort, the patients were only genotyped for the rs1990760 polymorphism of IFIH1. Single nucleotide polymorphisms (SNPs) were determined by a multiplex bead-based assay (CPH cohort) or real-time PCR (ODE cohort). Associations were investigated using the Cochran-Armitage trend test. The odds ratio (OR) for minor allele homozygotes versus major allele homozygotes suggested a protective effect of the IFIH1 rs1990760 SNP for SLE in the ODE cohort [OR 0.52, 95 % confidence intervals (95 % CI) 0.31-0.88, Pcorr. = 0.05] but not in the CPH cohort, although the OR suggested a trend in the same direction, and when combining the two patient cohorts, ORs were 0.57, 95 % CI 0.37-0.88. None of the other investigated polymorphisms showed any association with SLE. Regarding phenotypes, we found a statistically significant association between rs1990760 and malar rash in the CPH cohort, with ORs suggesting a protective effect (OR 0.28, 95 % CI 0.13-0.62 for heterozygotes and OR 0.11, 95 % CI 0.03-0.41 for homozygotes, Pcorr. = 0.0001). There were no significant associations between rs1990760 and presence of anti-dsDNA, anti-U1RNP, or anti-Smith antibodies. Our study supports previous findings of an association between the rs1990760 polymorphism of IFIH1 and SLE and indicates that this SNP may also be associated with malar rash in SLE patients although this finding needs confirmation.

Potential association of pulmonary tuberculosis with genetic polymorphisms of toll-like receptor 9 and interferon-gamma in a Chinese population

BackgroundAssociation studies have been employed to investigate the relationships between host single nucleotide polymorphisms (SNPs) and susceptibility to pulmonary Tuberculosis (PTB). However, such candidate genetic markers have not been widely studied in Chinese population, especially with respect to the disease development from latent M. tuberculosis infection (LTBI).MethodsIn this case–control study, 44 candidate SNPs were examined in a total of 600 participants (PTB patients, LTBI controls and healthy controls without M. tuberculosis infection) from Zhengzhou, China. The two groups of controls were frequency matched on gender and age with PTB patients. Genotyping was carried out by the Illumina Golden Gate assay.ResultsWhen comparing PTB patients with LTBI controls but not healthy controls without M. tuberculosis infection, significant associations with disease development were observed for TLR9 1174 A/G, TLR9 1635 A/G and IFNG 2109G/A. The two loci in TLR9 were in LD in our study population (r2=0.96, D’=1.00). A combined effect of the genotypes associated with increased risk of PTB (i.e. TLR9 1174G/G and IFNG 2109 A/A) was found when comparing PTB patients with LTBI controls (p=0.004) but not with healthy controls without infection (p=0.433).ConclusionsPotential associations between TLR9 and IFN-γ genetic polymorphisms and PTB were observed in a Chinese population which supports further study of the roles played by TLR9/IFN-γ pathway during the development of PTB.

TLR9 Promoter Polymorphism Is Associated with Both an Increased Susceptibility to Gastric Carcinoma and Poor Prognosis

ObjectiveGenetic polymorphisms of Toll-like receptors (TLRs) may influence the effects of H. pylori infection and play important roles in gastric carcinogenesis. The aim of this study was to determine whether the polymorphisms of TLR4 and TLR9 are associated with susceptibility to gastric carcinoma and its prognosis.MethodsThis study consisted of 314 patients with gastric cancer and 314 healthy controls. The polymorphisms were assessed using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis. Survival was analyzed by Kaplan–Meier survival curves.ResultsNo variant genotypes of TLR4+896A/G, TLR4+1196C/T, or TLR9 -1237T/C were detected. For TLR9 -1486 T/C, multiple logistic regression analyses revealed that compared with the TT homozygote, patients with both the TC variant (adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.04–2.10) and the CC variant (adjusted OR = 1.63, 95% CI = 1.01–2.64) had higher risks of gastric cancer. Further stratification analyses revealed that an increased risk of gastric cancer associated with C carriers was evident among females (adjusted OR = 1.84, 95%CI = 1.02–3.33), in younger subjects aged less than 60 years old (adjusted OR = 1.86, 95%CI = 1.15–3.00), and subjects with H. pylori infection (adjusted OR = 1.53, 95% CI = 1.03–2.27). We also observed a significant association between C carriers and noncardia gastric cancer (adjusted OR = 1.51, 95% CI = 1.03–2.20). In addition, we demonstrated that the C carrier genotype and H. pylori infection may have a synergistic effect and conferred an OR of 2.44 for developing gastric cancer. TLR9 -1486C was also identified as an independent marker of poor survival of carcinoma.ConclusionsOur results suggest that TLR9 -1486C carriers are associated with an increased risk and poor prognosis of gastric carcinoma in the Chinese population.