Toll-like Receptor 4 Rs1927911 Research Articles

Altered levels of IFN-γ, IL-4, and IL-5 depend on the TLR4 rs4986790 genotype in COPD smokers but not those exposed to biomass-burning smoke.

Chronic obstructive pulmonary disease (COPD) is associated with tobacco smoking and biomass-burning smoke exposure. Toll-like receptor 4 (TLR4) single-nucleotide polymorphisms (SNPs) may contribute to its pathogenesis. The study aimed to assess the association of rs4986790 and rs4986791 in the TLR4 gene in a Mexican mestizo population with COPD secondary to tobacco smoking (COPD-TS) and biomass-burning smoke (COPD-BBS) and to evaluate whether the genotypes of risk affect cytokine serum levels. We enrolled 2,092 participants and divided them into two comparisons according to their environmental exposure. SNPs were genotyped using TaqMan probes. Serum cytokine levels (IL-4, IL-5, IL-6, IL-10, and INF-γ) were quantified by ELISA. The rs4986790 AA genotype in COPD-TS was associated with a higher COPD risk (OR = 3.53). Haplotype analysis confirmed this association, identifying a block containing the rs4986790 allele (A-C, OR = 3.11). COPD-TS exhibited elevated IL-6, IL-4, and IL-5 levels compared with smokers without COPD (SWOC), whereas COPD-BBS displayed higher IFN-γ, IL-6, and IL-10 levels. The AA carriers in the COPD-TS group had elevated IL-4, IL-5, and IFN-γ compared with carriers of AG or GG. The rs4986790 common allele and the A-C haplotype (rs4986790-rs4986791) were associated with a higher COPD risk in smokers; COPD patients carrying the AA genotype showed increased pro-inflammatory cytokines.

Interaction of the TLR4 rs1927911 polymorphism with house dust mite sensitization in allergic rhinitis with its prognosis.

Sensitization to the house dust mite (HDM) plays important roles in the development of allergic rhinitis (AR). Toll-like receptor 4 (TLR4) is a key initiator of the innate immune system upon exposure to environmental factors. The present study investigated the independent and interaction effects of HDM sensitization and TLR4 rs1927911 polymorphism on AR and its prognosis in children. This study included 2,929 children (mean age, 7.8 yrs) from the Children's HEalth and Environmental Research study (CHEER), a prospective study with a 2-year-interval for 4 years. An ISAAC questionnaire was used with skin prick tests in all subjects. TaqMan genotyping was performed for TLR4 (rs1927911) polymorphism in 1,024 children. HDM sensitization increased risk of current AR (aOR, 2.50; 95% CI, 1.41-4.41; P for interaction = 0.005), current asthma at follow-up (aOR, 4.63; 95% CI, 2.41-8.88; P for interaction < 0.001) and allergic march (aOR, 2.57; 95% CI, 1.06-6.22; P for interaction = 0.002) by interacting with genotypes of TLR4 (rs1927911). HDM sensitization increased risk of persistence (aOR, 4.17; 95% CI, 1.77-9.83) and new diagnosis of AR (aOR, 2.48; 95% CI, 1.10-5.61), new sensitization to inhalant allergens (aOR, 10.67; 95% CI, 5.83-19.54), and new development of bronchial hyper-responsiveness (aOR, 5.29; 95% CI, 2.29-12.21) in children with CC genotype of TLR4 rs1927911. HDM sensitization affects AR and its prognosis by interacting with TLR4 rs1957911 polymorphism. The preventive and therapeutic strategies for AR in children need to be targeted in accordance with genetic susceptibility with HDM sensitization.

Frequency of Meningococcal Meningitis Susceptibility Associated TLR4 +896 A/G (rs4986790) Allele in the Saudi Population

Meningococcal meningitis (MM) is a severe central nervous system (CNS) infection that occurs primarily in children. MM can damage brain areas associated with hearing, learning, reasoning, focus, and memory. Genetic changes, including single nucleotide polymorphisms (SNPs), which compromise pathogen recognition increase the risk and severity of MM. There is little data on how the variation in the frequency of the rs4986790 polymorphism in the Toll-like receptor 4 (TLR4) gene may affect the population of Saudi Arabia. This study sought to determine the allelic frequency and distribution of the TLR4 rs4986790 A/G polymorphism in the Saudi population and compare the data to other global populations. Data from epidemiological studies conducted in various ethnic groups were extracted using PUBMED (Medline) and similar web databases. An estimated 5.88% of the Saudi population harbors the TLR4 rs4986790 G variant allele. This differed significantly from the frequencies in populations in China (p=0.0002), Japan (p=0.0001), Korea (p=0.0001), and Mexico (p=0.01). The TLR4 rs4986790 polymorphism variant allele has a unique pattern in the Saudi population, which may be the result of racial differences. These findings could assist in the risk assessment of people harboring the TLR4 +896 GG genotype susceptible to MM in the Saudi population.

Immune and inflammation-related gene polymorphisms and susceptibility to tuberculosis in Southern Xinjiang population: A case-control analysis.

Genetic and immune factors play an important role in tuberculosis. Under different ethnicities and genetic backgrounds, different immune and inflammation-related gene polymorphisms may confer different susceptibility to tuberculosis. This study investigated the relationship between immune and inflammation-related gene polymorphism and susceptibility to tuberculosis in Xinjiang Uyghur population, China. In this case-control study, we enrolled 507 pulmonary tuberculosis patients and 454 healthy controls from Southern Xinjiang. single nucleotide polymorphism (SNP) genotyping was performed. The 12 SNPs of nine immune and inflammation-related genes (including TNF rs361525, IL6 rs2066992 and rs1524107, IL17A rs3748067, IL17F rs763780, VDR rs731236, rs2228570 and rs1544410, IFNGR1 rs1327474, P2RX7 rs3751143, CTAGE1 rs4331426 and Toll-like receptor 4 (TLR4) rs4986790) and their relationship with tuberculosis were evaluated. The T allele and TT genotype of IL-6 rs2066992 and rs1524107 increased the risk of active tuberculosis. The C allele of IFNGR1 rs1327474 was related to the reduced risk of tuberculosis in the Xinjiang Uyghur population. The G allele and AG/GG genotypes of TLR4 rs4986790 were associated with an increased risk of tuberculosis (p<.05). Furthermore, haplotype analysis found that the haplotype TT of interleukin (IL)-6 was a risk factor, whereas the CG type was a protective factor for active tuberculosis in the Xinjiang Uyghur population. There were three immune and inflammation-related genes (IL-6, IFNGR1 and TLR4) and a total of four SNPs (rs2066992, rs1524107, rs1327474 and rs4986790) related to the susceptibility of the Uyghur population to tuberculosis. Our findings may provide evidence for further understanding the mechanism of tuberculosis susceptibility in the Xinjiang Uyghur population.

Risk factors for irreversible airway obstruction after infant bronchiolitis

BackgroundIncreasing evidence shows that environmental factors in childhood play a role in development of irreversible airway obstruction. We evaluated early-life and preschool-age risk factors for irreversible airway obstruction in adolescence after bronchiolitis in infancy. MethodsThis study is a secondary analysis of data collected during prospective long-term follow-up of our post-bronchiolitis cohort. Risk factor data were collected during hospitalisation and on follow-up visits at 5–7 and 10–13 years of ages. Lung function was measured from 103 participants with impulse oscillometry at 5–7 years of age and from 89 participants with flow-volume spirometry at 10–13 years of age. ResultsAsthma diagnosis at <12 months of age showed a significant association with irreversible airway obstruction at 10–13 years of age independently from current asthma. Irreversible airway obstruction was less frequent in children with variant than wild genotype of the Toll-like receptor 4(TLR4) rs4986790, but the significance was lost in logistic regression adjusted for current asthma and weight status. Higher post-bronchodilator respiratory system resistance at 5 Hz and lower baseline and post-bronchodilator reactance at 5 Hz by impulse oscillometry at 5–7 years of age were associated with irreversible airway obstruction at 10–13 years of age. ConclusionAsthma diagnosis during the first living year and worse lung function at preschool age increased the risk for irreversible airway obstruction at 10–13 years of age after bronchiolitis. TLR4 rs4986790 polymorphism may be protective for development of irreversible airway obstruction after bronchiolitis.

Association Between TLR4 Gene Polymorphisms and Risk of Preeclampsia: Systematic Review and Meta-Analysis

BackgroundToll-like receptor 4 (TLR4) plays a pivotal role in the innate immune response and is hyperactivated in preeclampsia (PE). Several researchers have published conflicting evidence for TLR4 rs4986790 and rs4986791 single nucleotide polymorphisms (SNPs) as risk factors for PE. The present meta-analysis was conducted to obtain a more definitive conclusion about the effects of these SNPs on PE susceptibility.Material/MethodsTo determine the correlation between rs4986790 and rs4986791 polymorphisms in the TLR4 gene and susceptibility to PE, the PubMed, Web of Science, EMBASE, Chinese National Knowledge Infrastructure, and Chinese WANFANG databases were searched for eligible articles. Statistical analysis was performed with STATA software, version 12.0. Pooled odds ratios with corresponding 95% confidence intervals (CIs) were extracted for assessment of correlation strength.ResultsWe identified 5 studies including 578 cases and 631 controls for the rs4986790 SNP and 4 studies including 469 cases and 457 controls for the rs4986791 SNP, mainly from a White population. The pooled analyses showed no statistical relationship between the polymorphisms rs4986790 and rs4986791 and PE susceptibility in 5 genetic models (all P>0.05). Moreover, the allelic and dominant gene models of rs4986790 and the allelic, heterozygous, and dominant gene models of rs4986791 had high heterogeneity. The sensitivity analysis explored potential sources of heterogeneity and confirmed the findings of this meta-analysis.ConclusionsTLR4 rs4986790 and rs4986791 polymorphisms may not be implicated in PE susceptibility, primarily in a White population. More high-quality studies of genetic associations with PE are warranted.

TLR4 T399I Polymorphism and Endometriosis in a Cohort of Italian Women

Background: Endometriosis is a widespread multifactorial disease in which environmental, genetic, and epigenetic factors contribute to the phenotype. Single Nucleotide Polymorphisms (SNPs) in genes implicated in pivotal molecular mechanisms have been investigated as susceptible risk factors in distinct populations. Among these, Toll-like receptor 4 (TLR4) represents a good candidate due to its role in the immune/inflammatory response and endometriosis pathogenesis. Methods: The TRL4 gene T399I SNP (C/T transition, rs4986791) was investigated in 236 Italian endometriosis patients and 150 controls by using the PCR-RFLP method. One-tailed Fisher’s exact test was used to compare differences between categorical variables. T399I genotype distribution was evaluated for Hardy–Weinberg equilibrium in both groups using the Chi-squared test for given probabilities. Results: Fisher’s exact test comparing C and T allele frequencies showed a difference in the frequency of T alleles between patients and controls (OR = 1.96, 95% confidence interval 0.91–4.23; p-value = 0.0552). Genotype frequencies did not show any significant difference between patients and controls. The homozygous TT genotype was observed in 2% of endometriosis women and not in controls. Conclusions: Our results show that the TLR4 rs4986791 T variant may be considered a genetic risk factor for endometriosis in Italian women. More extensive studies in other populations are needed to confirm this result.

Toll-like receptor 4 polymorphisms were associated with low serum pro-inflammatory cytokines in BCG osteitis survivors.

The aim of the study was to evaluate the association of Toll-like receptor 4 (TLR4) gene variations with osteitis risk after Bacillus Calmette-Guérin (BCG) vaccination given at birth and with serum cytokine levels measured in adulthood. We determined the TLR4 rs4986790 single-nucleotide polymorphism (SNP) in 132 study subjects with BCG osteitis in infancy and compared the genotype distributions and allele frequencies between them and population controls. Serum concentrations of 11 cytokines measured in adulthood were compared between study subjects with the wild vs variant TLR4 rs4986790 genotype. The genotypes and allele frequencies of the TLR4 rs4986790 SNP did not differ between BCG osteitis cases and population controls. Instead, subjects with the variant genotype presented with lower serum interleukin (IL) concentrations of the pro-inflammatory IL-6, IL-17A and IL-12 cytokines and with marginally lower interferon-γ concentrations, but with higher serum anti-inflammatory IL-4 concentration. The results concern also the TLR4 rs4986791, since these two SNPs are co-segregating in the Finnish population. The findings suggest that TLR4 has no significant role in the emergence of osteitis after newborn BCG vaccination, but the variant genotypes of the TLR4 rs4986790 and rs4986791 may impair the production of pro-inflammatory cytokines.

Dectin-1 rs3901533 and rs7309123 Polymorphisms Increase Susceptibility to Pulmonary Invasive Fungal Disease in Patients with Acute Myeloid Leukemia from a Chinese Han Population.

This study aimed to assess whether genetic variants of dendritic cell-associated C-type lectine-1 (Dectin-1), Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) influence the susceptibility to pulmonary invasive fungal disease (IFD) in patients with acute myeloid leukemia (AML) from a Chinese Han population. Eight single nucleotide polymorphisms (SNPs) of Dectin-1 (rs16910526, rs3901533, and rs7309123), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) and MyD88 (rs4988453 and rs4988457) in the genomic DNA of 172 adult AML patients were genotyped. Pulmonary IFD was diagnosed as proven or probable according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus guidelines. SNPs that were significant in the univariate analysis were further analyzed using the multiple logistic regression analysis to determine their association with the occurrence of pulmonary IFD. The mRNA expression of Dectin-1 was detected according to the genotype by quantitative realtime PCR (qRT-PCR), and the correlation of this expression with the occurrence of pulmonary IFD in AML patients was analyzed. Two Dectin-1 intron SNPs (rs3901533 and rs7309123) were found to be significantly associated with the susceptibility to pulmonary IFD in AML patients in a Chinese Han population. Significant associations were noted between pulmonary IFD and Dectin-1 rs3901533 dominant model (G/T+G/G vs. T/T, OR: 2.158; 95% CI: 1.109-4.2, P=0.02), Dectin-1 rs3901533 G allele (OR: 2.201; 95% CI: 1.206-4.019, P=0.01), or Dectin-1 rs7309123 C allele (OR: 1.919; 95% CI: 1.047-3.518, P=0.03). There were no significant associations between pulmonary IFD and the remaining Dectin-1 SNPs (rs16910526), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) or MyD88 (rs4988453 and rs4988457). In conclusion, two Dectin-1 SNPs (rs3901533 and rs7309123) are associated with increased susceptibility to pulmonary IFD in AML patients in a Chinese Han population.

Association of Toll‐like 4 receptor gene polymorphism (rs4986790, rs4986791) with the risk of urinary tract infection: A systematic review and meta‐analysis

Recently published studies had shown that there may be a potential link between the Single nucleotide polymorphism (SNP) of Toll-like receptor-4 (TLR4), and the risk of urinary tract infection (UTI); however, no consensus was reached. To further understand the relationship between TLR SNPs and urinary tract infections, we searched for related studies published in PubMed, EMBASE, and Web of Science before October 30, 2018, for further systematic review and meta-analysis. Our study accrued 10 case-control studies, which included 1476 urinary tract infection patients and 1449 healthy controls in TLR4(rs4986790, rs4986791). R3.4.2 and Stata 15.0 software were used for the analysis. In general, there was no statistically significant association between rs4986790 and urinary tract infection in the four genetic models. However, in the subgroup analysis, the Asian population showed significantly difference in the allelic model (G vs A: OR = 1.88 [95% CI:1.42-2.49], P = .03). In addition, there were also significant differences in the dominant model (GG + AG vs AA OR = 1.97 [95% CI:1.46-2.66], P = .01). Due to the small number of available literatures, no meaningful conclusion can be drawn regarding the relationship between TLR4 (rs4986791) and the risk of urinary tract infections in general. Nevertheless, our meta-analysis shows that in Asian populations, TLR4 (rs4986790) may be associated with risk of urinary tract infection.

The association of toll-like receptor 4 gene polymorphisms with primary open angle glaucoma susceptibility: a meta-analysis.

Primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) cause irreversible blindness while current medications cannot completely inhibit disease progression. An understanding of immunopathogenesis is thus a keystone to develop novel drug targets and genetic markers are still required for early diagnosis. Toll-like receptor 4 (TLR4) is an essential player in inflammation in various diseases. However, the TLR4 polymorphisms have not been completely elucidated in both types of glaucoma. The aim of the present study was to identify the association between TLR4 polymorphism and glaucoma (POAG and NTG) via the use of a comprehensive review and meta-analysis. The relevant studies were collected from PubMed, Excerpta Medica Database (EMBASE), and Web of Science to identify eight included articles, assessed for quality by a modified Newcastle-Ottawa Scale (NOS) for gene association study. A meta-analysis was applied to calculate the pooled odds-ratio and 95% confidence intervals (CIs) to evaluate the association between TLR4 polymorphism and glaucoma. The results revealed that TLR4 rs1927911 A/G, rs12377632 C/T, and rs2149356 G/T significantly decrease the risk of POAG and NTG in allele contrast models 0.71-, 0.71-, and 0.67-fold, respectively. Moreover, rs4986790 A/G and rs4986791 C/T showed a stringent association with POAG in allele contrast, heterozygous, recessive, and overdominant models. In conclusion, this meta-analysis represented a significant correlation between TLR4 polymorphisms and both types of glaucoma suggesting that TLR4 might be involved in the pathogenesis of glaucoma and may be applied as a genetic marker for disease screening.

Analysis of the Association of Polymorphisms rs5743708 in TLR2 and rs4986790 in TLR4 with Atopic Dermatitis Risk

ABSTRACTBackground: We carried out a meta-analysis to assess whether Toll-like receptor 2 (TLR2) rs5743708 and Toll-like receptor 4 (TLR4) rs4986790 polymorphisms are associated with the risk of atopic dermatitis.Methods: A systematic search of PubMed, Embase, and Web of Science was performed to identify eligible case–control studies on the association of rs5743708 and rs4986790 with the risk of atopic dermatitis. Statistical analyses of the odds ratio (OR), 95% confidence interval (CI), and p value were performed using STATA software.Results: Our meta-analysis included a total of nine case–control studies, all involving Caucasian populations. With respect to the TLR2 rs5743708 G/A polymorphism, there was a statistically significant difference in the overall risk of atopic dermatitis between the case and control groups [OR = 2.07, p value of association test, p(association) = 0.001 in allele (A vs. G) model; OR = 1.93, p(association) = 0.004 in carrier (A vs. G) model; OR = 2.07, p(association) = 0.001 in heterozygote (GA vs. GG) model; OR = 1.99, p(association) = 0.001 in dominant (GA+ AA vs. GG) model]. Similar positive results were observed in the subgroup analysis of “population-based control.” For the TLR4 rs4986790 A/G polymorphism, an increased atopic dermatitis risk was detected in the case group under the allele [OR = 1.78, p(association) = 0.013], carrier [OR = 1.69, p(association) = 0.027] and heterozygote [OR = 1.74, p(association) = 0.020] models, but not the dominant [OR = 1.44, p(association) = 0.070] model, in comparison to the population-based control group.Conclusion: Our meta-analysis revealed a novel finding that the heterogeneous “GA” genotype of the TLR2 rs5743708 and “AG” genotype of the TLR4 rs4986790 may be associated with increased susceptibility to atopic dermatitis in Caucasians.

Abstract 245: Genetic variation related to innate immunity and colorectal cancer risk

Abstract Introduction: Previous studies have shown that polymorphisms in the Toll-like receptor 4 (TLR4) gene may be associated with obesity, inflammatory bowel disease, and various cancers, including prostate, breast, and gastric cancer. However, the data regarding the associations between various TLR4 single-nucleotide polymorphisms (SNPs) and colorectal cancer (CRC) risk are inconsistent. In addition, the effect of interactions between TLR4 SNPs and obesity on the risk of CRC remains unclear. Methods: We selected candidate SNPs involved in the TLR4 pathway that were previously associated with the risk of CRC or other cancer (N=31). SNPs with low minor allele frequency (MAF &amp;lt; 0.05) were excluded (N=2), leaving 29 SNPs in the main analysis. We examined the associations of these SNPs with CRC risk using logistic regression on 10,998 cases of colorectal cancer and 10,691 controls drawn from 14 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). BMI was dichotomized into non-obese (BMI ≤25) and obese (BMI &amp;gt;25) categories. Overall and BMI-stratified analyses were performed across studies, with regression models adjusting for sex, age, study site, and the first three principal components from EIGENSTRAT to account for potential population substructure. A false discovery rate at 0.2 was applied to correct for multiple testing. Results: Before adjustment for multiple comparisons, TLR4 SNPs rs10116253, rs11536891, rs7873784, rs1927911, rs4986791, and rs4986790 were associated with CRC risk. Additionally, for both rs4986791 and rs4986790, this association was more pronounced in those with a BMI ≤25 (rs4986791 - OR: 1.17; 95% CI: 1.02-1.34; rs4986790 - OR: 1.20; 95% CI: 1.04-1.38) compared to those who had a BMI &amp;gt;25 (rs4986791 - OR: 1.03; 95% CI: 0.93-1.15; rs4986790 - OR: 1.03; 95% CI: 0.92-1.15). However, after accounting for multiple comparisons, there were no statistically significant associations between candidate SNPs and CRC nor any statistically significant SNP interactions with BMI. Conclusion: This large study provides evidence that neither these identified TLR4 SNPs nor their interaction with obesity are associated with CRC risk. Citation Format: Jessica Citronberg, Barbara Banbury, Andrew T. Chan, Peter T. Campbell, Graham Casey, Jenny Chang-Claude, Steven J. Gallinger, Tabitha Harrison, Michael Hoffmeister, Mark A. Jenkins, Loic Le Marchand, Hongmei Nan, Hongmei Nan, Li Jiao, Robert E. Schoen, Hermann Brenner, Emily White, Ulrike Peters, Polly A. Newcomb. Genetic variation related to innate immunity and colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 245.

Relationship between Arg753Gln Toll-like receptor 2 and Asp299Gly Toll-like receptor 4 genetic variations and susceptibility to colorectal cancer in Southern Iran

Variations in Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) encoding genes have been associated with tumorigenesis through the disruption of immune and inflammatory responses. The aims of this study were to evaluate the two single nucleotide polymorphisms (SNPs) of the genes Arg753Gln TLR2 (rs5743708) and Asp299Gly TLR4 (rs4986790) in colorectal cancer patients in southern Iran. Colorectal cancer patients and healthy controls were included in this study (150 Persian subjects in each group). Blood samples were used for genotyping by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between these SNPs and colorectal cancer and clinicopathological factors, including age, gender, tumor stage and differentiation were also investigated. A significant association was found between Arg753Gln TLR2 SNP and colorectal cancer. This SNP was significantly more frequent in male patients. However, there was no association between Asp299Gly TLR4 and colorectal cancer. Therefore, Arg753Gln TLR2 SNP can be considered as a risk factor for colorectal cancer incidence in southern Iran, especially in men. Further investigations in other populations are recommended in order to assess the association of this SNP with colorectal cancer.

Testing an association between TLR4 and CXCR1 gene polymorphisms with susceptibility to urinary tract infection in type 2 diabetes in north Indian population

BackgroundGenetic variations of Toll like receptor 4 (TLR4) and CXC-chemokine receptor type1 (CXCR1), the key elements of innate immune system and their association with urinary tract infection (UTI) were studied in general population. In present study we investigate genetic variation of these genes in diabetic patients (3 to 4 times higher prevalence of UTI in comparison to general population). MethodsA total 1100 subjects (318 diabetic patients with UTI, 324 diabetic patients without UTI, 200 non-diabetic UTI patients and 260 age matched healthy control) were enrolled in the study. SNPs of TLR4 rs4986790, rs4986791 and CXCR1 rs2234671 was assessed by PCR-RFLP and PCR-SSP respectively. ResultsStatistical analysis revealed that A/G genotype and G allele of TLR4 rs4986790 are significantly associated with UTI in both diabetics and nondiabetic patients in comparison to healthy control. Similarly CT genotype and T allele of TLR4 rs4986791 are also significantly associated with UTI in both groups. We also found that prevalence of A/G genotype of TLR4 rs4986790 and CT genotype of TLR4 rs4986791 are significantly higher in patients of diabetes with UTI in comparison to diabetic patients without UTI. We did not find any association of CXCR1 rs2234671 polymorphism with UTI by comparing with any group. ConclusionWe found that TLR4 rs4986790 and rs4986791 gene polymorphism is a risk for UTI development in both diabetic and nondiabetic patients in north Indian population.

Prenatal Second-Hand Smoke Increases Atopic Dermatitis in Children withTNF-α/TLR4/GSTP1Polymorphisms

Although second-hand smoke (SHS) exposure is associated with asthma, its effect on eczema is unclear. Especially, the effect of maternal passive smoking on childhood eczema has rarely been studied. Polymorphisms in tumor necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4), and glutathione S-transferase P1 (GSTP1) genes interact with air pollutants and modify allergic disease development. This study aimed to investigate the effect of gene–environment interactions between SHS exposure and TNF-α/TLR4/GSTP1 polymorphisms on childhood eczema. From 2005 to 2006, 3,639 children aged 7 or 8 years were enrolled and followed up 2 years later. Details of SHS exposure and eczema were collected by questionnaires. TNF-α (rs1800629), TLR4 (rs1927911), and GSTP1 (rs1695) genotypes were determined. Maternal passive smoking during pregnancy was associated with increased prevalence of eczema diagnosis ever (adjusted odds ratio [aOR] 1.50, 95% confidence intervals [CI] 1.25–1.79), and eczema symptoms in the past 12 months...

The relationship between asthma and bronchiolitis is modified by TLR4, CD14, and IL‐13 polymorphisms

Asthma is a complex genetic disorder that is associated with both genetic and environmental factors. The aim of study was to investigate the combined effect of toll-like receptor 4 (TLR4), cluster of differentiation 14 (CD14), and interleukin-13 (IL-13) polymorphisms and bronchiolitis in the development of childhood asthma. A modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was used to survey 1,341 elementary school children and 919 nursery children in Seoul, Korea. TLR4 (rs1927911), CD14 (rs2569190), and IL-13 (rs20541) polymorphisms were genotyped by the TaqMan assay. In elementary school and nursery children, parental history of asthma (adjusted odds ratio [aOR] 2.56 [95% CI 1.16-5.63], aOR 3.60 [95% CI 1.66-7.76], respectively), and past history of bronchiolitis (aOR 3.11 [95% CI 1.84-5.24], aOR 3.94 [95% CI 2.27-6.84], respectively) were independent risk factors for asthma diagnosis. When compared to children with each CC of TLR4 polymorphism or TT of CD14 polymorphism or GG of IL13 polymorphism and no past history of bronchiolitis, children with CT or TT of TLR4 polymorphism and past history of bronchiolitis had 4.23 and 5.34 times higher risk to develop asthma, respectively; children with TT of CD14 polymorphism and past history of bronchiolitis had 3.57 and 7.22 times higher risk for asthma, respectively; children with GA or AA of IL-13 polymorphism and past history of bronchiolitis had 3.21 and 4.13 times higher risk for asthma, respectively. Family history of asthma or allergic rhinitis and past history of bronchiolitis could be independent risk factors for the development of childhood asthma. The relationship between asthma and bronchiolitis is modified by the TLR4, CD14, and IL-13 polymorphisms in Korean children.

Association of Toll-Like Receptor 4 Polymorphisms with Diabetic Foot Ulcers and Application of Artificial Neural Network in DFU Risk Assessment in Type 2 Diabetes Patients

The Toll-Like receptor 4 (TLR4) plays an important role in immunity, tissue repair, and regeneration. The objective of the present work was to evaluate the association of TLR4 single nucleotide polymorphisms (SNPs) rs4986790, rs4986791, rs11536858 (merged into rs10759931), rs1927911, and rs1927914 with increased diabetic foot ulcer (DFU) risk in patients with type 2 diabetes mellitus (T2DM). PCR-RFLP was used for genotyping TLR4 SNPs in 125 T2DM patients with DFU and 130 controls. The haplotypes and linkage disequilibrium between the SNPs were determined using Haploview software. Multivariate linear regression (MLR) and artificial neural network (ANN) modeling was done to observe their predictability for the risk of DFU in T2DM patients. Risk genotypes of all SNPs except rs1927914 were significantly associated with DFU. Haplotype ACATC (P value = 9.3E − 5) showed strong association with DFU risk. Two haplotypes ATATC (P value = 0.0119) and ATGTT (P value = 0.0087) were found to be protective against DFU. In conclusion TLR4 SNPs and their haplotypes may increase the risk of impairment of wound healing in T2DM patients. ANN model (83%) is found to be better than the MLR model (76%) and can be used as a tool for the DFU risk assessment in T2DM patients.

Toll Like Receptor 4 D299G Associates with Disease Progression in Caucasian Patients with Chronic HBV Infection: Relationship with Gender

This study aimed to verify whether rs4986790 A > G single nucleotide polymorphism of toll like receptor 4 (TLR-4) associates with a more severe course of hepatitis B virus (HBV) chronic infection. A cross-sectional study enrolled 191 Caucasian HBV-positive patients: 28 HBsAg + inactive carriers, 121 chronic hepatitis B, 42 HBsAg + transplant candidates. A longitudinal study included 94 patients followed-up for a median time of 19.3 years. TLR-4 rs4986790 A/A genotype was carried less frequently in male HBsAg + inactive carriers than in males with HBsAg + active chronic infection (12/17 Vs 109/121, p = 0.022). At stepwise logistic regression analysis, the carriage of TLR-4 rs4986790 A/A genotype was found to be and independent predictor of liver fibrosis (O.R. 14.8, p = 0.019). In conclusion, in HBV-positive Caucasian patients, the A/A genotype of the rs4986790 polymorphism may influence a worse outcome of chronic HBV infection, mainly through a synergistic interaction with male gender.

Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy

The clinical course of patients with dilated cardiomyopathy (DCM) varies from cardiac recovery to end stage heart failure. The etiology of this variability is largely unknown. In this study, we investigated the impact of coding polymorphisms of the innate immune protein Toll-like receptor 4 (TLR4) on left ventricular performance in patients with DCM. Two variants of TLR4 (rs4986790, TLR4 c.1187A→G, p.299D→G and rs4986791,TLR4 c.1487C→T, p.T399I) were investigated in 158 patients with DCM. Other reasons for heart failure were excluded by coronary angiography, myocardial biopsy, and echocardiography. Risk factors, age, gender, or treatment did not differ among the groups. At the follow-up evaluation (median 4.0-5.4 months), patients carrying the TLR4 wild type gene displayed cardiac recovery under intense medical heart failure therapy indexed by reduced left ventricular dilation, improved left ventricular ejection fraction, and reduced NT-probrain natriuretic peptide blood level when compared with the initial evaluation. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular ejection fraction (p = 0.006) and left ventricular dilation (p = 0.015) at the follow-up evaluation when compared with carriers of the wild type gene under the same treatment conditions. In addition, NT-probrain natriuretic peptide level in carriers of both TLR4 variants did not change significantly at the follow up when compared with the first evaluation. Among patients with DCM, the presence of the TLR4 variants rs4986790 and rs4986791 predicts impaired cardiac recovery independently of medical treatment or cardiac risk factors.