Variation In Toll-like Receptors Research Articles

Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus

Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.

Genetic Variation in Toll-Like Receptors (TLRs) 2, 4, and 9 Influences HIV Disease Progression Toward Active TB and AIDS.

Toll-like receptors (TLRs) are identified as one of the key components of the innate immune system. The objective of this study was to explore the influence of genetic variability in these TLRs on human immunodeficiency virus (HIV) disease progression with and without tuberculosis (TB) co-infection. This prospective, cross-sectional, and longitudinal study included 373 HIV-positive patients without TB infection. This study aimed to examine the genetic variation in TLRs (TLR2, TLR4, and TLR9) between patients with HIV-1 infection and those who progressed to active TB during the two years of follow-up. During the two year follow-up of 373 positive patients, 98 patients progressed to active TB/AIDS (acquired immunodeficiency syndrome). When comparing 98 HIV patients who developed active TB/AIDS to 275 HIV patients who did not, it was discovered that the frequency of the A allele in TLR9 was considerably higher (p <0.001) in HIV patients progressed to active TB/AIDS. Ninety eight HIV individuals who advanced to active TB/AIDS showed a significantly higher frequency of the AA genotype in TLR9 than did in HIV patients who had no TB/AIDS (p <0.001). The increased association of the AA genotype of TLR9 in HIV patients who progressed to active TB during follow-up suggests that HIV-positive patients with the AA genotype of TLR9 have increased susceptibility towards TB during the disease progression.

Bioinformatics analysis to identify the relationship between human papillomavirus-associated cervical cancer, toll-like receptors and exomes: A genetic epidemiology study.

Genetic variants may influence Toll-like receptor (TLR) signaling in the immune response to human papillomavirus (HPV) infection and lead to cervical cancer. In this study, we investigated the pattern of TLR expression in the transcriptome of HPV-positive and HPV-negative cervical cancer samples and looked for variants potentially related to TLR gene alterations in exomes from different populations. A cervical tissue sample from 28 women, which was obtained from the Gene Expression Omnibus database, was used to examine TLR gene expression. Subsequently, the transcripts related to the TLRs that showed significant gene expression were queried in the Genome Aggregation Database to search for variants in more than 5,728 exomes from different ethnicities. Cancer and HPV were found to be associated (p<0.0001). TLR1(p = 0.001), TLR3(p = 0.004), TLR4(221060_s_at)(p = 0.001), TLR7(p = 0.001;p = 0.047), TLR8(p = 0.002) and TLR10(p = 0.008) were negatively regulated, while TLR4(1552798_at)(p<0.0001) and TLR6(p = 0.019) were positively regulated in HPV-positive patients (p<0.05). The clinical significance of the variants was statistically significant for TLR1, TLR3, TLR6 and TLR8 in association with ethnicity. Genetic variants in different TLRs have been found in various ethnic populations. Variants of the TLR gene were of the following types: TLR1(5_prime_UTR), TLR4(start_lost), TLR8(synonymous;missense) and TLR10(3_prime_UTR). The "missense" variant was found to have a risk of its clinical significance being pathogenic in South Asian populations (OR = 56,820[95%CI:40,206,80,299]). The results of this study suggest that the variants found in the transcriptomes of different populations may lead to impairment of the functional aspect of TLRs that show significant gene expression in cervical cancer samples caused by HPV.

The role of toll-like receptors in orchestrating osteogenic differentiation of mesenchymal stromal cells and osteoimmunology

Osteoimmunology is a concept involving molecular and cellular crosstalk between the skeletal and immune systems. Toll-like receptors (TLRs) are widely expressed both on mesenchymal stromal cells (MSCs), the hematopoietic cells, and immune cells in the osteogenic microenvironment for bone development or repair. TLRs can sense both exogenous pathogen-associated molecular patterns (PAMPs) derived from microorganisms, and damage-associated molecular patterns (DAMPs) derived from normal cells subjected to injury, inflammation, or cell apoptosis under physiological or pathological conditions. Emerging studies reported that TLR signaling plays an important role in bone remodeling by directly impacting MSC osteogenic differentiation or osteoimmunology. However, how to regulate TLR signaling is critical and remains to be elucidated to promote the osteogenic differentiation of MSCs and new bone formation for bone tissue repair. This review outlines distinct TLR variants on MSCs from various tissues, detailing the impact of TLR pathway activation or inhibition on MSC osteogenic differentiation. It also elucidates TLR pathways’ interplay with osteoclasts, immune cells, and extracellular vesicles (EVs) derived from MSCs. Furthermore, we explore biomaterial-based activation to guide MSCs’ osteogenic differentiation. Therefore, understanding TLRs’ role in this context has significant implications for advancing bone regeneration and repair strategies.

Molecular Effect of Variants in Toll-like Receptor 4 Gene in Saudi Patients with Type 2 Diabetes Mellitus.

Single-nucleotide polymorphisms (SNPs) in the Toll-like receptor 4 (TLR4) gene have been documented in type 2 diabetes mellitus (T2DM) and other diseases in the Saudi population. We investigated the relationship between rs11536889, rs4986790, and rs4986791 SNPs in the TLR4 gene and T2DM in the Saudi population; 105 patients with T2DM and 105 healthy controls were analyzed. The TLR4 gene was amplified through PCR, followed by restriction fragment length polymorphism analysis for rs4986791 and Sanger sequencing for rs11536889 and rs4986790 SNPs. The clinical and biochemical characteristics were associated with T2DM (p < 0.05). The rs11536889, rs4986790, and rs4986791 SNPs in control subjects followed the Hardy-Weinberg equilibrium (p > 0.05). Alleles were associated with rs11536889, rs4986791, heterozygous codominant, and dominant models (p < 0.05). However, the rs4986790 SNP was not associated with T2DM (p > 0.05). Logistic regression analysis showed that high-density lipoprotein cholesterol (HDLc) levels were associated with T2DM (p < 0.001). Analysis of variance showed that waist (p = 0.0005) and hip circumferences (p = 0.002) in rs4986790 and rs4986791 SNPs, in SBP (p = 0.001), DBP (p = 0.002), and HDLc levels (p = 0.003), were associated with T2DM subjects. T2DM was also associated with the haplotype (p < 0.001) but not with linkage disequilibrium. The gene-gene interaction was associated with the three SNPs studied in patients with T2DM according to the generalized multifactor dimensionality reduction model (p < 0.0001). Dendrogram and graphical depletion analysis revealed a moderate association in patients with T2DM. The results suggest that rs11536889 and rs4986790 SNPs are genotypically and allelically associated with T2DM in Saudi patients. Future functional studies are recommended to validate the genetic roles of these SNPs in the pathogenesis and progression of diseases.

Genetic variation in toll-like receptor 4 gene with primary antiphospholipid syndrome susceptibility: a cohort of Egyptian patients

BackgroundAs toll-like receptor 4 (TLR4) plays important roles in cellular immunity and TLR4 polymorphisms have been shown to be associated with susceptibility to a range of diseases, the present study aimed to investigate the association between TLR4 gene polymorphisms and the incidence of primary antiphospholipid syndrome (PAPS).MethodsTwo TLR4 single nucleotide polymorphisms (rs4986790 and rs4986791) were assessed in 110 subjects of Egyptian ethnicity, including 65 female patients with PAPS and 45 matched healthy controls, using polymerase chain reaction-restriction fragment length polymorphism. Results were verified using automated sequencing.ResultsThe homozygous wild-type (AA, aspartic acid) rs4986790 variant and (CC, threonine) rs4986791 variant were the predominant genotypes in the control and PAPS groups.ConclusionThe results of this preliminary study of TLR4 gene variants among patients with PAPS in an Egyptian population found no association between the rs4986790 and rs4986791 variants and susceptibility to PAPS.

Association of toll-like receptors polymorphisms with COPD risk in Chinese population.

Background: Previous studies have reported that the Toll-like receptors (TLRs) are related with the progress of chronic obstructive pulmonary disease (COPD). We aimed to explore the association of TLRs single nucleotide polymorphisms (SNPs) and COPD risk. Methods: 170 COPD patients and 181 healthy controls were enrolled in this case-control study. MassARRAY platform was used for genotyping seven tagging SNPs (TLR2: rs3804100, rs4696480, rs3804099; TLR3: rs3775290, rs3775291, rs5743305; TLR9: rs352140) of TLRs. The correlations between the SNPs and COPD risk were determined using logistic regression. Results: We found that the rs3775291 of TLR3 significant decreased the risk of COPD (TT versus CC: non-adjusted OR = 0.329, 95% CI = 0.123-0.879, p = 0.027). In the genetic models analysis, the rs3775291 was associated with a decreased effect of COPD based on the recessive model (TT versus CC/CT: non-adjusted OR = 0.377, 95% CI = 0.144-0.988p = 0.047). The rs4696480 of TLR2 gene was associated with a decreased risk of COPD after adjustment by age and gender (TA versus AA: adjusted OR = 0.606, 95% CI = 0.376-0.975, p = 0.039). Conclusion: Our study showed that genetic variants in TLRs were associated with risk of COPD. The rs3775291 and rs4696480 may act as a potential biomarker for predicting the risk of COPD in Chinese population.

Selection Balancing at Innate Immune Genes: Adaptive Polymorphism Maintenance in Toll-Like Receptors

Balancing selection is a classic mechanism for maintaining variability in immune genes involved in host–pathogen interactions. However, it remains unclear how widespread the mechanism is across immune genes other than the major histocompatibility complex (MHC). Although occasional reports suggest that balancing selection (heterozygote advantage, negative frequency-dependent selection, and fluctuating selection) may act on other immune genes, the current understanding of the phenomenon in non-MHC immune genes is far from solid. In this review, we focus on Toll-like receptors (TLRs), innate immune genes directly involved in pathogen recognition and immune response activation, as there is a growing body of research testing the assumptions of balancing selection in these genes. After reviewing infection- and fitness-based evidence, along with evidence based on population allelic frequencies and heterozygosity levels, we conclude that balancing selection maintains variation in TLRs, though it tends to occur under specific conditions in certain evolutionary lineages rather than being universal and ubiquitous. Our review also identifies key gaps in current knowledge and proposes promising areas for future research. Improving our understanding of host–pathogen interactions and balancing selection in innate immune genes are increasingly important, particularly regarding threats from emerging zoonotic diseases.

Neuroinflammation Upregulated Neuronal Toll-Like Receptors 2 and 4 to Drive Synucleinopathy in Neurodegeneration.

Background: Parkinson’s disease (PD) is characterized by intraneuronal α-synuclein aggregation called Lewy bodies and progressive dopaminergic neurodegeneration. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation. The molecular link on how neuroinflammation upregulates neuronal TLRs and induces accumulation of α-synuclein aggregates to drive synucleinopathy remains to be determined. Objective: Despite conditioned medium from microglia and TLR agonists were utilized to study their effects on neuronal cells, a Transwell coculture system, comprising lipopolysaccharide-activated microglia on top and retinoic acid-differentiated SH-SY5Y cells at the bottom more mimicking in vivo neuroinflammation, was employed to elucidate the mechanism of activated microglia on neuronal cells. Methods: Genetic variants of TLRs in PD patients were genotyped and the multiplex cytokines, sRAGE, and HMGB1were assessed. A coculture system was employed to measure α-synuclein aggregates and neurite shortening by confocal microscope. The expression of TLR2/4 and autophagy flux was detected by western blot and immunofluorescence. Results: PD patients showed higher plasma levels of proinflammatory cytokines and genetic TLR4 variant, c.896 A > G (p. D299G). Elevated proinflammatory cytokines in coculture medium was also seen. Phosphorylation and aggregation of α-synuclein, shortening of neurite, upregulation of TLR2/4 expression, activation of downstream p38 and JNK, and dampening of autophagic flux were seen in SH-SY5Y cells cocultured with activated microglia. Those were prevented by inhibiting TLR2/4 and p38/JNK signaling. Conclusion: Activated microglia-derived neuroinflammation induced neuronal TLR2/4-p38/JNK activation to perturb autophagy, causing accumulation of α-synuclein aggregates and neurite shortening. Targeting neuronal TLR2/4 pathway might be a mechanistic-based therapy for neurodegenerative disease, such as PD.

Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

Variants of Toll-like receptor 6 associated with tuberculosis susceptibility in the Chinese Tibetan population

BackgroundOur investigation attempted to understand the role of innate immunity related genes played in tuberculosis. The relationship between single-nucleotide polymorphisms (SNPs) of three innate immunity-related genes (TLR6, MyD88, and TIRAP) and tuberculosis (TB) risk in two Chinese populations were explored. MethodsTotally 1185 Chinese Han, consisting of 580 active TB cases and 605 healthy controls (HCs), and 1216 Chinese Tibetan individuals including 613 TB patients and 603 HCs were enrolled to conduct two case-control studies. TagSNPs of the three genes were selected based on the HapMap database and genotyped by the SNPscan™ Kit. Haploview software 4.2 was applied to perform linkage disequilibrium (LD) analysis and online software SHEsis was used to discover significant haplotype block. RegulomeDB and HaploReg were applied to predict potential functional SNPs of the three genes. ResultsThe results showed that minor alleles of rs5743808 and rs5743827 of TLR6 were related with increased TB risk (p = 0.001, OR 95%CI = 1.51 (1.18–1.95) and p = 0.002, OR 95%CI = 1.42 (1.14–1.77)), and significant association was also observed between rs5743827 and TB risk in male subgroup (p = 0.003, OR 95%CI = 1.67 (1.91–2.35)) in the Tibetan population. For the Tibetan population, frequency of haplotype ACGT of rs1039559-rs3775073-rs5743808-rs5743827 of TLR6 was significantly higher in the TB group (p = 0.0008), while haplotype ATAC was significantly higher in the control group (p = 0.0002). The above associations remained after permutation and Bonferroni correction. No significant association was found in the Han population. Probable functions of tagSNPs of TLR6 and some other linked variants were discovered after bioinformatic analysis. ConclusionsThis study suggested that variants of TLR6 might be associated with TB risk in the Tibetan population, while not in the Han population. The difference between Chinese Han and Tibetan people will provide better understanding of tuberculosis.

Genetic variations of toll-like receptors: Impact on susceptibility, severity and prognosis of bacterial meningitis.

Bacterial meningitis (BM) is a serious infectious disease of the central nervous system，which is mainly caused by Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Group B Streptococcus and Listeria monocytogenes. Throughout the world, BM has become one of the most lethal diseases that commonly occurs in children. Toll like receptors (TLRs) are one of the most important immune defense lines in infectious diseases, and play an essential role in host defense. Accumulating evidence shows that genetic variations in TLRs are associated with host responses in BM. This review aims to summarize the role of different TLRs and their genetic variations in the susceptibility, severity and prognosis of BM and discuss the identified risk factors for better treatment and improvement of the course and outcome of BM.

A genetic variant in toll-like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis.

Bacterial translocation drives liver disease progression. We investigated whether functional genetic variants in toll-like receptor 5 (TLR5), the receptor for bacterial flagellin, affect the risk for hepatocellular carcinoma (HCC). Healthy controls (n=212), patients with alcohol abuse without liver disease (n=382), and patients from a discovery cohort of alcohol-associated cirrhosis (n=372 including 79 HCC cases), a validation cohort of alcohol-associated cirrhosis (n=355 including 132 HCC cases), and a cohort of cirrhosis due to nonalcoholic steatohepatitis (NASH) (n=145 including 62 HCC cases) were genotyped for the TLR5 rs5744174 and rs5744168 polymorphisms. Chemokine levels were measured by ELISA in patients' sera and supernatants of flagellin-stimulated healthy monocytes. Frequency of the TLR5 rs5744174 TT genotype was similar in healthy controls (33%), controls with alcohol abuse (34%), and patients with alcohol-associated cirrhosis in the discovery (28%), validation (33%), and NASH cohort (31%). The TT genotype was enriched in patients with versus without HCC in the discovery, validation, and NASH cohort (41% vs 25%; 39% vs 29%; 40% vs 24%; p<.05 each). This genotype remained a risk factor for HCC (OR=1.9; p=.01) after multivariate correction for age, gender, diabetes, and carriage of the PNPLA3 148M variant. Interleukin-8 induction in monocytes from healthy controls and serum levels of interleukin-8 and CXCL1 from cirrhotic patients with the TT genotype were significantly increased versus C allele carriers. The TLR5 rs5744174 polymorphism, affecting immune response to flagellin, is linked to occurrence of HCC in cirrhosis caused by steatohepatitis.

Toll-Like Receptors Gene Polymorphisms in Autoimmune Disease.

Toll-like receptors (TLRs) are important initiators of the immune response, both innate and acquired. Evidence suggests that gene polymorphisms within TLRs cause malfunctions of certain key TLR-related signaling pathways, which subsequently increases the risk of autoimmune diseases. We illustrate and discuss the current findings on the role of Toll-like receptor gene polymorphisms in numerous autoimmune diseases in this review, such as type 1 diabetes mellitus, Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. The study of genetic variation in TLRs in different populations has shown a complex interaction between immunity and environmental factors. This interaction suggests that TLR polymorphisms affect the susceptibility to autoimmune diseases differently in various populations. The identification of Toll-like receptor gene polymorphisms can expand our understanding of the pathogenesis of autoimmune diseases, which will subsequently guide effective medical management and provide insight into prognosis and advanced treatments.

TLRs in Mycobacterial Pathogenesis: Black and White or Shades of Gray.

Toll-like receptors (TLRs) play critical role in the innate recognition of pathogens besides orchestrating innate and adaptive immune responses. These receptors exhibit exquisite specificity for different pathogens or their products and, through a complex network of signalling, generate appropriate immune responses. TLRs induce both pro- and anti-inflammatory signals depending on interactions with the adapter molecules thereby impacting the outcome of infection. Hence, TLR signalling ought to be stringently regulated to avoid harmful effects on the host. Mycobacteria express antigens which are sensed by TLRs leading to activation of various signalling molecules important for initiating the death of infected cells and containment of pathogens. Conversely, it also utilizes TLRs for immune evasion and persistence. Due to the enormous diversity in the repertoire of virulence traits expressed by mycobacteria, genetic variations in TLRs often impair the host's ability to respond to mycobacterial-stress, affecting health and disease manifestations. Thus, understanding TLR signalling is of great importance for insights into host-mycobacterial interactions and designing effective measures for controlling the spread and persistence of the bacterium.

Association of TLR4 gene polymorphisms with sepsis after a burn injury: findings of the functional role of rs2737190 SNP.

Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated response to an infection that is common among patients with moderate to severe burn injury. Previously, genomic variants in Toll-like receptor 4 (TLR4), a key innate immunity receptor, have been associated with sepsis and infection susceptibility. In this study, the association of six TLR4 SNPs with sepsis after burn injury was tested in the Mexican mestizo population. We found that the rs2737190 polymorphism is associated with sepsis after burn trauma. Interestingly, the G allele and GG genotype were associated with a lower risk of developing sepsis. Since the rs2737190 SNP is in the promoter region of the TLR4 gene, we analyzed the possibility that this polymorphism regulates the TLR4 pathway. We cultured peripheral blood mononuclear cells from different genotype carriers and found, after stimulation with LPS, that carriers of the GG genotype showed a higher expression of TLR4, IL6, and TNFα than AA genotype carriers. The results suggest that the GG genotype produces an increase in the TLR4 expression, and therefore an improvement in the immune response. We conclude that the rs2737190 polymorphism may become a useful marker for genetic studies of sepsis in patients after a burn injury.

The Role of Toll-Like Cell Receptor 2 (Arg753gln) Polymorphism in Allergen Sensitization and Disease Severity in Atopic Dermatitis Patients

Background: Variations in Toll-like receptor 2 (TLR2) encoding gene have been associated with atopic conditions. Objective: The present work aims to analyze single nucleotide polymorphism (SNP) of TLR2 gene Arg753Gln in atopic dermatitis (AD) and its association with allergen sensitization and disease severity. Methodology: 110 AD patients and 75 healthy controls were enrolled and subjected to genotyping of TLR2 gene Arg753Gln by restriction enzyme analysis and allergy investigations. Results: TLR2 Arg753Gln SNP was significantly more frequent in the patients (48%) in comparison to the healthy group (32%) (0R= 1.7). Individuals with the G/A genotype were at a higher risk for AD development by two times. Inhalant allergens specific IgE were distinguished in 80 % of patients with TLR2 gene polymorphism. Conclusion: GA genotype of TLR2 gene is more dominant in severe cases of atopic dermatitis and associated with sensitization to certain inhalant allergens as house dust mites and pollens.

Genetic variation in toll like receptors 2, 7, 9 and interleukin-6 is associated with cytomegalovirus infection in late pregnancy

BackgroundMaternal cytomegalovirus (CMV) infection and/or reactivation in pregnancy is associated with a myriad of adverse infant outcomes. However, the role of host genetic polymorphisms in modulating maternal CMV status is inconclusive. This study investigated the possible association of single nucleotide polymorphisms in toll-like receptor (TLR) and cytokine genes with maternal plasma CMV DNA status in black Zimbabweans.MethodsIn a cross-sectional study, 110 women in late gestation who included 36 CMV infected cases and 74 CMV uninfected, age and HIV status matched controls were enrolled. Twenty single nucleotide polymorphisms in 10 genes which code for proteins involved in immunity against CMV were genotyped using Iplex GOLD SNP genotyping protocol on the Agena MassARRAY® system. Statistical analyses were performed using Stata SE and the ‘Genetics’ and ‘SNPassoc’ packages of the statistical package R.ResultsThe TLR7 rs179008A > T (p < 0.001) polymorphism was associated while the TLR9 rs352139T > C (p = 0.049) polymorphism was on the borderline for association with CMV positive (CMV+) status. In contrast, the interleukin (IL)-6 rs10499563T > C (p < 0.001) and TLR2 rs1816702C > T (p = 0.001) polymorphisms were associated with CMV negative (CMV-) status. Furthermore, allele frequencies of SNPs in TLR2, TLR4, TLR9, TLR7, IL-6, IL-10, IL-28B, IL-1A and interferon AR1 (IFNAR1) genes are being reported here for the first time in a Zimbabwean population. The allele frequencies in the Zimbabwean population are generally comparable to other African populations but different when compared to European and Asian populations.ConclusionsToll-like receptor and interleukin genetic polymorphisms influence CMV status in late gestation among black Zimbabweans. This is attributable to possible modulation of immune responses to CMV reactivation in a population previously exposed to CMV infection.

Impact of Genetic Variation in TLR4 3'UTR on NSCLC Genetic Susceptibility.

Toll-like receptors (TLRs) are expressed not only in immune cells but also in a variety of tumor cells. Single-nucleotide polymorphisms (SNPs) located in the TLRs' promoter or the 3′ untranslated region may affect gene expression by affecting the activity of the promoter or regulating the binding of mRNA to miRNA. This study aimed to investigate the association of the SNPs in TLR genes with the susceptibility to NSCLC. This case-control study involved 700 lung cancer patients and 700 healthy controls. All individuals were genotyped for all selected SNPs in TLR genes using polymerase chain reaction (PCR) test-based restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP genotyping assay. The association of genetic variations in TLRs with the susceptibility to NSCLC was evaluated by unconditional logistic regression with OR (95% CI). After evaluating transcriptional factor or miRNA binding capability by bioinformatics methods, six TLRs were identified for further analysis. We did not find that TLR3 rs5743303, TLR4 rs1927914, TLR4 rs11536891, TLR5 rs1640816, and TLR7 rs3853839 were associated with NSCLC risk (P > 0.05). Our data showed that TLR4 rs7869402 C > T polymorphism reduced the risk of NSCLC with OR (95% CI) of 0.63 (0.45–0.89). When stratified by gender and age, the individuals carrying at least one rs7869402T allele significantly decreased the NSCLC risk among males (OR = 0.58, 95% CI = 0.38–0.87) and among youngsters (OR = 0.43, 95% CI = 0.27–0.69). Smoking stratification analysis showed that the rs7869402T allele-containing genotype reduced the risk of NSCLC with OR (95% CI) of 0.50 (0.29–0.87) among smokers but not among nonsmokers (P > 0.05). When the individuals were classed by the pathological type, we found that the rs7869402T-containing genotype was associated with the risk of adenocarcinoma (OR = 0.62, 95% CI = 0.41–0.92) but not with that of squamous cell carcinoma (OR = 0.71, 95% CI = 0.44–1.13) and other types (OR = 0.23, 95% CI = 0.03–1.70). Compared with the TLR4 Ars1927914-Crs7869402-Trs11536891 haplotype, the Grs1927914-Trs7869402-Trs11536891 haplotype was associated with a decreased risk for developing NSCLC with OR (95% CI) of 0.57 (0.41–0.80). These results indicated that the TLR4 rs7869402 variation affects the genetic susceptibility to NSCLC.

Polymorphisms of TLR9 gene are associated with a decreased risk of H. pylori infection in a Chinese population.

BackgroundA series of evidence suggests that genetic variation in toll-like receptor (TLR) 9 might influence the outcome of Helicobacter pylori (H. pylori) infection and play an important role in gastric carcinogenesis.MethodsWe conducted a case-control study to evaluate TLR9 polymorphisms on the risk of H. pylori infection and non-cardia gastric cancer (GC) in a Chinese population. We genotyped a tagging single-nucleotide polymorphism (SNP), rs164640, and a potentially functional SNP, rs187084, by TaqMan technique among 288 patients with non-cardia GC and 281 controls. Unconditional logistic regression (LR) was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for SNPs in association with H. pylori infection and non-cardia GC risk.ResultsOur results indicated that among normal controls, the minor allele homozygotes of both SNPs were significantly associated with a decreased risk of H. pylori infection when compared with their major allele homozygotes (for rs164640: OR =0.41, 95% CI, 0.18–0.93; for 187084: OR =0.38, 95% CI, 0.17–0.85). However, neither of the two SNPs demonstrated a significant association with non-cardia GC risk.ConclusionsOur results revealed that TLR9 polymorphisms might have effects on the risk of H. pylori infection, but they do not seem to contribute to the risk of non-cardia GC in our studied population.