Toll-like receptor 2 and Toll-like receptor 4 polymorphisms in invasive pneumococcal disease

BACKGROUND: Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and trigger anti-microbial host defense responses. Several in vitro and in vivo studies in mice indicate that TLR2 and TLR4 are involved in the defense against Streptococcus pneumoniae. Studies have revealed associations between polymorphisms in TLRs and human diseases. The effect of polymorphisms in TLR2 and TLR4 in the human defense to S. pneumoniae has not been studied. METHODS: We genotyped 99 Caucasian patients with invasive pneumococcal disease and 178 Caucasian controls for the known R579H, P631H and R753Q polymorphisms in TLR2 and the D299G polymorphism in TLR4 with PCR-RFLP methods. RESULTS: The distribution of the TLR2 R579H, P631H and R753Q and TLR4 D299G variants was not significantly different between the patients and the controls. After stratification of the patient population by age, sex, diagnosis, and mortality no significant differences for the TLR2 R753Q genotype and TLR4 D299G genotype were found between various patient subgroups and between patient subgroups and the control population. It should be mentioned that for the TLR2 polymorphisms neither the control group nor the patient group contains homozygous mutant individuals. CONCLUSION: We found no association between TLR2 and TLR4 polymorphisms and invasive pneumococcal infection.     

Toll-like receptor polymorphisms and vasculitis susceptibility: meta-analysis and systematic review

The aim of this study was to determine whether toll-like receptor (TLR) polymorphisms confers susceptibility to vasculitis. A literature search was conducted using the PubMed and Embase. A meta-analysis on the associations between the TLR4 Asp299Gly polymorphisms and vasculitis was carried out using allele contrast, dominant, and codominant models and a systematic review of other TLR polymorphisms. Fourteen studies involving 2,064 patients and 2,481 controls were included in this systematic review, which comprised nine on Behcet’s disease (BD), three on giant cell arteritis (GCA), and one on Henoch–Schenlein purpura (HSP). Meta-analysis of six studies showed a significant association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis and GCA (Odds ratio [OR] = 1.368, 95 % confidence interval [CI] = 1.300–1.815, p = 0.030; OR = 1.523, 95 % CI = 1.099–2.112, p = 0.012). Under a random effects model, the adjusted ORs calculated using the trim and fill technique revealed an association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis (OR = 1.544, 95 % CI = 1.091–2.185, p < 0.05). Stratification by vasculitis type using the codominant model showed the trend for the association with GCA (OR = 1.569, 95 % CI = 0.970–2.538, p = 0.066). There were three studies on the TLR2 Arg753Gln polymorphism and two on the TLR4 Thr399Ile polymorphism; no association with vasculitis was evident. Among the TLR2, TLR7, and TLR9 polymorphisms included in this review, one Asian study revealed a significant association between the TLR7 rs5743733 and rs3853839 with BD (p = 0.002, 0.036) and one Asian study showed an association of TLR9 rs352140 with BD (p = 0.009). This meta-analysis demonstrates that the TLR4 Asp299Gly polymorphism may confer susceptibility to GCA. The review of published data suggests that other TLR polymorphisms such as TLR7 and TLR9 may play a role in vasculitis.     

Toll-like receptor (TLR) and matrix metalloproteinase (MMP) polymorphisms and periodontitis susceptibility: a meta-analysis

The aim of this study was to determine whether the toll-like receptor (TLR) and matrix metalloproteinase (MMP) polymorphisms confers susceptibility to periodontitis in ethnically different populations. A literature search using PubMed and Embase provided the data to conduct a meta-analysis on the associations between the TLR2 Arg753Gln, TLR4 Asp299Gly, Thr399Ile, MMP-1 ?1607 G1/G2 and MMP-9 ?1562 C/T polymorphisms and periodontitis. A total of 32 studies (14 on TLR polymorphisms and 18 on MMP polymorphisms) were considered in the meta-analysis. The meta-analysis showed no association between periodontitis and the TLR2 753Arg allele (Odds ratio [OR] = 0.962, 95 % confidence interval [CI] = 0.662–1.400, p = 0.841). Meta-analysis of the TLR4 Asp299Gly and Thr399Ile polymorphisms showed no association between periodontitis and the TLR4 299Asp allele in all study subjects (OR = 0.984, 95 % CI = 0.761–1.271, p = 0.900; OR = 1.030, 95 % CI = 0.748–1.418, p = 0.854). Meta-analysis showed an association between the MMP-1 ?1607 G2G2 genotype and periodontitis in Asians (OR = 3.778, 95 % CI = 1.210–11.80, p = 0.022). Meta-analysis containing only studies in Hardy–Weinberg equilibrium revealed no association between chronic periodontitis and the MMP-9 ?1562TT genotype (OR = 0.638, 95 % CI = 0.265–1.533, p = 0.315). This meta-analysis demonstrates a lack of association between the TLR2 Arg753Gln, TLR4 Asp299Gly, Thr399Ile, MMP-9 ?1562 C/T polymorphisms and periodontitis, but shows an association between the MMP-1 ?1607 G2G2 genotype and periodontitis in Asians.     

Effect of additional disease (Comorbidity) on association of allergic rhinitis with KCNE4 gene rs12621643 variant

Analysis of association of allergic rhinitis with the KCNE4 gene rs12621643 variant was conducted in Russian residents of West Siberia (taking into account comorbidity with bronchial asthma). It was found that, among individuals without bronchial asthma, the frequencies of the KCNE4*G allele and KCNE4*G/G genotype are significantly higher in patients with rhinitis compared to individuals without it. At the same time, no association of rs12621643 with rhinitis was detected in the group of individuals with bronchial asthma. The data obtained indicate the association of the KCNE4 gene variability with allergic rhinitis, although the effect of this gene relative to the development of the disease can be leveled against a background of the manifestation of another atopic disease.     

Bacterial lipopolysaccharide signaling through Toll-like receptor 4 suppresses asthma-like responses via nitric oxide synthase 2 activity

Asthma results from an intrapulmonary allergen-driven Th2 response and is characterized by intermittent airway obstruction, airway hyperreactivity, and airway inflammation. An inverse association between allergic asthma and microbial infections has been observed. Microbial infections could prevent allergic responses by inducing the secretion of the type 1 cytokines, IL-12 and IFN-gamma. In this study, we examined whether administration of bacterial LPS, a prototypic bacterial product that activates innate immune cells via the Toll-like receptor 4 (TLR4) could suppress early and late allergic responses in a murine model of asthma. We report that LPS administration suppresses the IgE-mediated and mast cell-dependent passive cutaneous anaphylaxis, pulmonary inflammation, airway eosinophilia, mucus production, and airway hyperactivity. The suppression of asthma-like responses was not due to Th1 shift as it persisted in IL-12(-/-) or IFN-gamma(-/-) mice. However, the suppressive effect of LPS was not observed in TLR4- or NO synthase 2-deficient mice. Our findings demonstrate, for the first time, that LPS suppresses Th2 responses in vivo via the TLR4-dependent pathway that triggers NO synthase 2 activity.     

Toll样受体2及Toll样受体4在大鼠实验性变应性鼻炎中的表达

目的研究Toll样受体2（Toll-like receptor2,TLR2）及Toll样受体4（TLR4）在实验性变应性鼻炎大鼠鼻黏膜中的表达及脂多糖（Lipopolysaccharide,LPS）对其表达的影响。方法SD大鼠48只随机分为正常对照组（A组）;变应性鼻炎组（B组）：经腹腔注射及鼻腔滴入卵清白蛋白（Ovalbumin,OVA）建立变应性鼻炎（Allergic rhinitis,AR）模型;变应性鼻炎＋LPS刺激组（C组）：大鼠激发成变应性鼻炎模型后再以LPS滴鼻。用逆转录聚合酶链反应（RT-PCR）方法检测鼻黏膜中TLR2 mRNA、TLR4 mRNA的表达。结果B、C组大鼠均成功激发为AR动物模型;各组鼻黏膜中均有TLR2 mRNA、TLR4 mRNA表达;各组间TLR2 mRNA的表达差异无统计学意义（P〉0．05）。B、C组TLR4 mRNA的表达较A组高（P〈0．01）;C组TLR4 mRNA表达较B组增高（P〈0．01）。结论AR大鼠有TLLR4的表达增高;LPS刺激后TLR4表达进一步增高,说明TLR4可能参与AR的发病。TLR2在AR大鼠中的表达未见增高;LPS刺激后。TLR2表达未见进一步增高,TLR2与变应性鼻炎的关系有待进一步研究。     

Influence of common non-synonymous Toll-like receptor 4 polymorphisms on bronchopulmonary dysplasia and prematurity in human infants

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease and major risk factor for severe respiratory syncytial virus (RSV) infection among preterm infants. The Toll-like receptor 4 (TLR4) is involved in oxidative injury responses in the lungs. Two non-synonymous single nucleotide polymorphisms in the TLR4 gene have been associated with RSV infection in children. However, it is unclear to what extent this association is confounded by BPD or prematurity. In this study, we analyzed two population-based cohorts of preterm infants at risk for BPD as well as ethnicity-matched infants born at term, to test whether the TLR4 polymorphisms Asp299Gly (rs4986790) and Thr399Ile (rs4986791) are independently associated with BPD or premature birth. In a Canadian cohort (n = 269) composed of a majority of Caucasian preterm infants (BPD incidence of 38%), the TLR4-299 heterozygous genotype was significantly under-represented in infants without BPD (1.6% of infants versus 12% in infants with severe BPD) after adjusting for twins, ethnicity, gestational age, birth weight and gender (p = 0.014). This association was not replicated in a Finnish cohort (n = 434) of premature singletons or first-born siblings of Caucasian descent, although the incidence of BPD was substantially lower in this latter population (15%). We did not detect a significant association (>2-fold) between TLR4 genotypes and prematurity (p>0.05). We conclude that these TLR4 genotypes may have, at best, a modest influence on BPD severity in some populations of high-risk preterm infants. Further studies are warranted to clarify how clinical heterogeneity may impact genetic susceptibility to BPD.     

Association of Toll-like receptor 4 gene polymorphism and expression with urinary tract infection types in adults

Background

Innate immunity of which Toll-like receptor (TLR) 4 and CXCR1 are key elements plays a central role in the development of urinary tract infection (UTI). Although the relation between the genetics of TLR4 and CXCR1 and UTI is investigated partly, the polymorphisms and expression of TLR4 and CXCR1 in different types of UTI in adults are not extremely clear.

Methodology/Principal Findings

This study investigates the presence of TLR4 A (896) G and CXCR1 G (2608) C polymorphisms in 129 UTI patients using RFLP-PCR. Gene and allelic prevalence were compared with 248 healthy controls. Flow cytometry was used to detect TLR4 and CXCR1 expression in the monocytes of UTI patients and healthy controls. TLR4 (896) AG genotype and TLR4 (896) G allele had higher prevalence in UTI (especially in acute cystitis and urethritis) patients, whereas CXCR1 (2608) GC genotype and CXCR1 (2608) C allele had lower prevalence in UTI patients than controls. TLR4 expression was significantly lower in chronic UTI patients than in acute pyelonephritis or healthy controls. CXCR1 expression was similar in both controls and patients. TLR4 expression in chronic UTI patients after astragalus treatment was higher than pre-treatment.

Conclusions

The results indicate the relationship between the carrier status of TLR4 (896) G alleles and the development of UTI, especially acute cystitis and urethritis, in adults. TLR4 expression levels are correlated with chronic UTI.     

Relationship between surfactant protein A polymorphisms and allergic rhinitis in a Chinese Han population

The development of allergic rhinitis is considered to be determined by the interaction between genetic and environmental factors. Surfactant protein A (SP-A), a member of the collectin family of proteins, plays an important role in immune regulation. The purpose of this study was to investigate the association between SP-A polymorphisms and allergic rhinitis. We conducted a case–control association study on a Chinese Han population, comprising 216 adult individuals with AR and 84 healthy controls. A total of 9 single-nucleotide polymorphisms (SNPs) mapped to the SP-A were genotyped using PCR-based molecular identification methods. The frequency of A allele at amino acid 223 in the patient group was significantly higher than that in the control group after correcting for multiple testing (P = 0.006). The 1A² allele haplotype in SFTPA2 was associated with decreased risk for allergic rhinitis, after applying Bonferroni corrections (P = 0.003). However, genetic variants of the SFTPA1 genes were not found to be associated with AR. In addition, no significant associations were established between any of the 9 SFTPA gene polymorphisms and the skin-prick test responses (P > 0.05). Further, no association was established between the 9 SNP loci and the levels of total serum immunoglobulin E (IgE) (P > 0.05). These results indicate that the gene polymorphism at the residue 223 in the carbohydrate recognition domain of SFTPA2 may be a genetic marker for the development of AR in the adult Chinese Han population.     

Polymorphisms in vitamin D receptor,toll-like receptor 2 and Toll-Like receptor 4 genes links with Dengue susceptibility

Host genetic factors are known to determine disease susceptibility in dengue virus infection. Therefore, in this study association of gene polymorphisms of Vitamin D Receptor [rs731236 (Taq) and rs7975232 (Apa1)], Toll-like receptor 2 [rs5743708 (Arg735Gln) and rs5743704 (Pro631His)] and Toll-like receptor 4 [rs4986790A/G(Asp299Gly13843) and rs4986791 C/T(Thr399Ile)] were studied in cases with dengue as compared to controls. Total 98 cases of confirmed dengue virus infection and 98 age, sex and geographically matched healthy controls were enrolled and their genetic polymorphisms for the above mentioned regions were studied by Sanger sequencing. Mutant genotypes CC of VDR rs731236 (Taq1) [(OR 3.808, p value =0.02, CI 1.160-12.498)], GG of VDR rs7975232 (Apa1) [(OR 3.485, p value =0.02, CI 1.162-10.45)] and heterozygous genotypes of TLR4 rs4986790 A/G Asp299Gly [OR 2.40, p value= 0.02, CI 1.12-5.14], TLR4 rs4986791 C/T Thr399Ile [OR 2.09, p value=0.02, CI 1.12-5.14] were found to be significantly more in cases with dengue virus infection as compared to the controls. Also, at these positions mutant alleles were observed in significantly higher number of cases than controls. The values for C allele at VDR rs731236 (Taq1) were OR 1.86, p value 0.009, CI 1.162-3.001; for allele G at rs7975232( Apa1) were OR 2.71, p value 0.006, CI 1.196-2.98 for allele G at TLR4s rs4986790 A/G Asp299Gly were OR 2.35, p value 0.009, CI 1.23-4.50 and for allele T at rs4986791 C/T Thr399Ile were OR 2.36, p value=0.006, CI 1.28-4.38. VDR and TLR4 but not TLR2 gene polymorphisms were found to be associated with dengue susceptibility in Indian population.     

Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection

Toll-like receptor (TLR)-4 is an important pattern recognition receptor for Candida albicans, playing a role in innate host defense. We investigated whether there is an association between the TLR4 Asp299Gly or TLR4 Thr399Ile polymorphism, and the occurrence of Candida bloodstream infection. We performed a case-control study, involving 43 patients with a Candida bloodstream infection and 166 healthy individuals. TLR4 Asp299Gly and Thr399Ile polymorphisms were assessed, as well as cytokine production after stimulation of peripheral blood mononuclear cells (PBMC) with Candida albicans. We observed that the prevalence of TLR4 Asp299Gly polymorphism was found to be higher in patients with Candida bloodstream infection than in controls (26% versus 10%; OR 3.0; 95%CI 1.3-6.9). All patients bearing the Asp299Gly polymorphism were also positive for the Thr399Ile allele, a linkage well described in literature. IL-10 production was higher in C. albicans-stimulated PBMC from volunteers bearing the TLR4 Asp299Gly polymorphism, and a similar tendency was observed in TLR4 Asp299Gly heterozygous patients who had recovered from candidemia. These findings show that the TLR4 Asp299Gly/Thr399Ile polymorphisms are associated with an increased susceptibility to Candida bloodstream infections, and an increased production of IL-10 is probably involved in this effect.     

顺尔宁对变应性鼻炎患者血清肺表面活性蛋白A、D动态水平影响及近 期疗效观察

目的:探讨顺尔宁对变应性鼻炎患者体内肺表面活性蛋白A、D水平的影响及近期疗效观察。方法:纳入的变应性鼻炎患者分成单纯变应性鼻炎患者组不伴哮喘组106例,变应性鼻炎伴哮喘患者组75例,健康成人组20例作为实验对照组。连续应用顺尔宁8周后,统计患者鼻部总体症状评分,以及血清SP-A、SP-D水平的动态变化情况。结果:单纯变应性鼻炎组、变应性鼻炎伴哮喘组患者治疗4周后、8周后与治疗前比较,鼻部总体症状评分均明显降低,差异均有统计学意义(均P0.05)。治疗4周后,单纯变应性鼻炎组、变应性鼻炎伴哮喘组患者血清SP-A、D水平较治疗前,差异无统计学意义(均P0.05);治疗8周后,单纯变应性鼻炎组、变应性鼻炎伴哮喘组患者血清SP-A、D水平较治疗前明显下降(均P0.05)。结论:顺尔宁可影响变应性鼻炎患者体内SP-A、SP-D水平,改善鼻部不适的症状。     

Toll-like receptor (TLR2, TLR4 and TLR5) gene polymorphisms and Helicobacter pylori infection in children with and without duodenal ulcer

Helicobacter pylori infection is mainly acquired in childhood, and polymorphisms in the host genes coding for Toll-like receptors (TLRs) may influence the innate and adaptive immune response to the infection, affecting the susceptibility to H. pylori or the disease outcomes. Our aim was to investigate whether TLR4, TLR2, and TLR5 polymorphisms were associated with H. pylori susceptibility and risk for duodenal ulcer in children. Gastric biopsy specimens were obtained at endoscopy for evaluation of H. pylori status, TLR4, TLR2 and TLR5 polymorphisms from 486 children (254 H. pylori-negative and 232 H. pylori-positive: 72 with and 160 without duodenal ulcer). cagA status of H. pylori infection was investigated by PCR. The levels of gastric cytokines were detected by ELISA. H. pylori-positivity or duodenal ulcer were not associated with TLR2, TLR4 or TLR5 polymorphisms. Otherwise, the presence of TLR4 polymorphic allele was associated with infection by cagA-positive strains and with increased gastric levels of interleukin-8 and interleukin-10. TLR4 polymorphism might ultimately contribute to more severe consequences of the infection in adulthood since it was associated with susceptibility to cagA-positive H. pylori infection early in life.     

Multi-symptom asthma is closely related to nasal blockage,rhinorrhea and symptoms of chronic rhinosinusitis-evidence from the West Sweden Asthma Study

Background

We have previously shown that approximately 25% of those with asthma in West Sweden have multiple asthma symptoms, which may describe a group of patients with more severe disease. Furthermore, asthma is associated with several co-morbid diseases, including rhinitis and chronic rhinosinusitis. The aim of this study was to determine whether multi-symptom asthma is related to signs of severe asthma, and to investigate the association between multi-symptom asthma and different symptoms of allergic and chronic rhinosinusitis.

Methods

This study analyzed data on asthma symptoms, rhinitis, and chronic rhinosinusitis from the 2008 West Sweden Asthma Study, which is an epidemiologically based study using the OLIN and GA²LEN respiratory and allergy focused questionnaires.

Results

Multi-symptom asthma was present in 2.1% of the general population. Subjects with multi-symptom asthma had more than double the risk of having night-time awakenings caused by asthma compared with those with fewer asthma symptoms (P < 0.001). The prevalence of allergic rhinitis was similar in the fewer- and multi-symptom asthma groups, but nasal blockage and rhinorrhea were significantly increased in those with multi- versus fewer-symptom asthma (odds ratio 2.21; 95% confidence interval 1.64-2.97, versus 1.49; 1.10-2.02, respectively). Having any, or one to four symptoms of chronic rhinosinusitis significantly increased the risk of having multi- versus fewer-symptom asthma (P < 0.01).

Conclusion

An epidemiologically identified group of individuals with multiple asthma symptoms harbour to greater extent those with signs of severe asthma. The degree of rhinitis, described by the presence of symptoms of nasal blockage or rhinorrhea, as well as the presence of any or several signs of chronic rhinosinusitis, significantly increases the risk of having multi-symptom asthma.     

CARD15 and TLR4 polymorphisms in atopic bronchial asthma

In order to investigate whether single nucleotide polymorphisms G(+2722)C and 3020insC of CARD15 and Asp299Gly of TLR4 contribute to atopic bronchial asthma, we performed a comparative analysis of allele and genotype frequencies of these polymorphisms in Russian patients from Moscow. DNA specimens obtained from 283 patients with atopic bronchial asthma and 227 healthy donors were genotyped. Neither G(+2722)C or 3020insC in CARD15 nor Asp299Gly in TLR4 were associated with asthma; CARD15 polymorphisms were not also associated with asthma severity. A haplotype frequency analysis of CARD15 polymorphisms did not detect significant differences between the groups studied. However, a strong association was found between Asp299Gly and asthma course: the Asp allele was associated with mild disease, while the minor Gly allele was associated with moderate/severe asthma (OR = 0.47, 95% CI [0.24–0.93] and OR = 2.12, 95% CI [1.08–4.18], respectively).     

Toll-like receptor 4 genetic diversity among pig populations

The transmembrane glycoprotein encoded by the Toll-like receptor 4 gene ( TLR4 ) acts as the transducing subunit of the lipopolysaccharide receptor complex of mammals, which is a major sensor of infections by Gram-negative bacteria. As variation in TLR4 may alter host immune response to lipopolysaccharide, the association between TLR4 polymorphisms and immune traits of the respiratory and gut systems has important implications for livestock. Here, a sequence dataset from 259 animals belonging to commercial and traditional European pig populations, consisting of 4305 bp of TLR4, including the full transcribed region, a portion of intron 2 and the putative promoter region, was used to explore genetic variation segregating at the TLR4 locus. We identified 34 single nucleotide polymorphisms, 17 in the coding sequence and 17 in the non-coding region. Five non-synonymous mutations clustered within, or in close proximity to, the hypervariable domain of exon 3. In agreement with studies in other mammals, a major exon 3 haplotype segregated at high frequency in the whole sample of 259 pigs, while variants carrying non-synonymous substitutions showed frequencies ranging between 0.6% and 8.7%. Although results on exon 3 provided suggestive evidence for purifying selection occurring at the porcine TLR4 gene, the analysis of both coding and non-coding regions highlighted the fact that demographic factors strongly influence the tests of departure from neutrality. The phylogenetic analysis of TLR4 identified three clusters of variation (ancestral, Asian, European), supporting the evidence of Asian introgression in European main breeds and the well documented history of pig breed domestication previously identified by mtDNA analysis.     

V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function

Asthma is a complex polygenic disease. Many studies have implicated the importance of IL-4R alpha in the development of allergic inflammation and its gene has been implicated in the genetics of asthma and atopy. In this study, we examined the functional consequences of two of the human IL-4R alpha allelic variants that have been found to associate with asthma and atopy. We examined the effects of each variant alone and in combination on IL-4-dependent gene induction. We found that neither the Q576R nor the I75V variants affected IL-4-dependent CD23 expression. However, the combination of V75R576 resulted in expression of an IL-4R alpha with enhanced sensitivity to IL-4. We next examined the genetics of five of the known IL-4R alpha allelic variants in asthmatic and nonatopic populations. Strikingly, the association of V75/R576 with atopic asthma was greater than either allele alone and the association of R576 with atopic asthma was dependent on the coexistence of V75. A haplotype analysis revealed a single IL-4R alpha haplotype that was associated with allergic asthma, VACRS, further confirming the importance of the V75 and R576 combination in the genetics of asthma. This is the first report demonstrating that a functional alteration in IL-4R alpha requires the coexistence of two naturally occurring single nucleotide polymorphisms (snps) in combination; neither snp alone is sufficient. These data illustrate the importance of studying snps in combination, because the functional significance of a given snp may only be evident in a specific setting of additional snps in the same or different genes.     

Association of inherited variation in Toll-like receptor genes with malignant melanoma susceptibility and survival

The family of Toll-like receptors (TLRs) is critical in linking innate and acquired immunity. Polymorphisms in the genes encoding TLRs have been associated with autoimmune diseases and cancer. We investigated the genetic variation of TLR genes and its potential impact on melanoma susceptibility and patient survival. The study included 763 cutaneous melanoma cases recruited in Germany and 736 matched controls that were genotyped for 47 single nucleotide polymorphisms (SNPs) in 8 TLR genes. The relationship between genotype, disease status and survival was investigated taking into account patient and tumor characteristics, and melanoma treatment. Analysis of 7 SNPs in TLR2, 7 SNPs in TLR3 and 8 SNPs in TLR4 showed statistically significant differences in distribution of inferred haplotypes between cases and controls. No individual polymorphism was associated with disease susceptibility except for the observed tendency for TLR2-rs3804099 (odds ratio OR  = 1.15, 95% CI 0.99–1.34, p = 0.07) and TLR4-rs2149356 (OR = 0.85, 95% CI 0.73–1.00, p = 0.06). Both polymorphisms were part of the haplotypes associated with risk modulation. An improved overall survival (Hazard ratio HR 0.53, 95% CI 0.32–0.88) and survival following metastasis (HR 0.55, 95% CI 0.34–0.91) were observed in carriers of the variant allele (D299G) of TLR4-rs4986790. In addition various TLR2, TLR4 and TLR5 haplotypes were associated with increased overall survival. Our results point to a novel association between TLR gene variants and haplotypes with melanoma survival. Our data suggest a role for the D299G polymorphism in the TLR4 gene in overall survival and a potential link with systemic treatment at stage IV of the disease. The polymorphic amino acid residue, located in the ectodomain of TLR4, can have functional consequences.     

TLR4 896A/G gene polymorphism, rather than the TLR4 1196C/T and TLR2 2258G/A gene polymorphisms, determines the severe and aggravated course of atopic dermatitis in children

The frequencies of the TLR2 gene 2258G/A and the TLR4 gene 1196C/T and 896A/G polymorphisms in children with atopic dermatitis (AD) were studied against controls. It was established after analyzing the distribution of the TLR2 and TLR4 genotypes and alleles that the TLR4 gene’s mutant 896G allele is reliably more frequently detected in children with AD who are susceptible to acute respiratory viral infections (9.3%), compared to the control group (χ² = 4.33; p = 0.038). An analysis of the clinical manifestations of the disease and their associations has shown a higher frequency of its mild course (p = 0.0001) in children with AD who have normal body resistance and of a moderately severe course (p = 0.0033), as well as of concomitant allergic rhinitis (AR) and/or bronchial asthma (BA) (p = 0.0355) and concomitant AR (p = 0.0673), in AD patients with higher susceptibility to acute respiratory viral infections. A severe course of the disease (p = 0.0485), associated with adenoid vegetation in combination with AR and/or BA (p = n0.0248) and concomitant adenoid vegetation in combination with AR (p = 0.0053), was more frequent in AD patients with the TLR4 gene’s mutant 896G allele, compared to patients with a “wild”-type allele.     

Toll-like receptor 4 (TLR4) polymorphisms in Iranian patients with visceral leishmaniasis

The role of Toll-like receptor (TLR) 4 in visceral leishmaniasis (VL), a disease caused by an obligate intracellular protozoan parasites belonging to the genus Leishmania, has been shown in the recent leishmaniasis experimental studies. As genetic host factors play an important role in the susceptibility and/or resistance to VL, the association between TLR4 gene mutations [A896G and C1196T single nucleotide polymorphisms (SNPs)] and VL was investigated. Genotyping of A896G (Asp299Gly) and C1196T (Thr399Ile) SNPs was performed in the patients with VL (N?=?122) and ethnically matched controls (N?=?155) using polymerase chain reaction–restriction fragment length polymorphism method. When VL patients and the controls were compared, no statistically significant differences were observed in A896G and C1196T alleles and genotypes (P?>?0.05). The TLR4 A896G and C1196T were in moderate linkage disequilibrium in the controls and patients (r ²?=?0.497, 0.548 and D′?=?0.705, 0.808, respectively), and haplotypes reconstructed from these SNPs were not significantly different between the aforementioned study groups. In conclusion, based on the results, TLR4 gene polymorphisms at the positions 896 and 1196 cannot be regarded as the major contributors to VL susceptibility among the Iranian population.