TLR4 Rs4986790 Research Articles

Associations of toll-like receptor polymorphisms with systemic lupus erythematosus: A meta-analysis

ObjectiveThe objective of this study was to examine whether polymorphisms in toll-like receptors 7 and 4 (TLR7 and 4) contribute to vulnerability to systemic lupus erythematosus (SLE). MethodsWe searched MEDLINE, Embase, and Web of Science for relevant articles and performed a meta-analysis to investigate the relationship between TLR7 rs179008, rs3853839, rs1790010, TLR4 rs4986791, and rs798690 polymorphisms and SLE. ResultsEighteen studies and 16 papers including 8022 patients with SLE and 9822 healthy controls were retrieved. Meta-analysis revealed that the TLR7 rs179008 T variant was not associated with SLE (OR = 1.008, 95% CI = 0.849–1.394, P = 0.504). Ethnic classification revealed no association between the TLR7 rs179008 T gene and SLE in either European or Latin American groups. Additionally, homozygous comparison, recessive, and dominant models revealed no association between the TLR7 rs179008 variant and SLE. In contrast, a significant association between SLE and the TLR7 rsrs3853839 GG + GA allele (OR = 2.135, 95% CI = 1.502–3.035, <0.001; OR = 23.20, 95% CI = 14.13–38.08, <0.001) was observed in the Arab and Asian groups. The T variant of TLR7 rsrs179010 was also associated with SLE in Asians (OR = 1.177, 95% CI = 1.048–1.321, P = 0.006). In contrast, the TLR4 rs4986791 variant was not associated with SLE in Europeans when allele, homozygous comparison, recessive, and dominant models were used. Furthermore, no association between the TLR4 rs4986790 variant and SLE risk in Europeans was found using any genomic model. ConclusionsMeta-analysis revealed that the TLR7 rs3853839 variant is associated with SLE risk in Asians and Arabs and that TLR7 rs179010 is associated with SLE in Asians. However, TLR7 rs179008, TLR4 rs4986791, and TLR rs798690 polymorphisms were not associated with SLE risk.

The single nucleotide polymorphism rs4986790 (c.896A>G) in the gene TLR4 as a protective factor in corona virus disease 2019 (COVID-19).

Several factors, such as hypertension and diabetes mellitus, are known to influence the course of coronavirus disease 2019 (COVID-19). However, there is currently little information on genetic markers that influence the severity of COVID-19. In this study, we specifically investigated the single nucleotide polymorphism (SNP) rs4986790 in the TLR4 gene to identify a universal marker for preclinical prediction of COVID-19 disease progression. We analyzed the influence of demographics, pre-existing conditions, inflammatory parameters at the time of hospitalization, and TLR4 rs4986790 genotype on the outcome of COVID-19 in a comprehensive cohort (N = 1570). We performed multivariable analysis to investigate the impact of each factor. We confirmed that younger patient age and absence of pre-existing conditions were protective factors against disease progression. Furthermore, when comparing patients with mild SARS-CoV-2 infection with patients who required hospitalization or intensive care or even died due to COVID-19, the AG/GG genotype of TLR4 rs4986790 was found to be a protective factor against COVID-19 disease progression (OR: 0.51, 95% CI: 0.34 - 0.77, p = 0.001). In addition, we demonstrated that low levels of interleukin-6 (IL-6) and procalcitonin (PCT) had a favorable effect on COVID-19 disease severity. In the subsequent multivariable analysis, we confirmed the absence of cardiovascular disease, low levels of IL-6 and PCT, and TLR4 rs4986790 AG/GG genotypes as independent predictors of potential hospitalization and reduction of severe or fatal disease course. In this study, we identified an additional genetic factor that may serve as an invariant predictor of COVID-19 outcome. The TLR4 rs4986790 AG/GG genotype reduced by half the risk of COVID-19 patients requiring hospitalization, intensive care or to have a fatal outcome. In addition, we were able to confirm the influence of previously known factors such as pre-existing conditions and inflammatory markers upon the onset of disease on the course of COVID-19. Based on these observations, we hereby provide another prognostic biomarker that could be used in routine diagnostics as a predictive factor for the severity of COVID-19 prior to SARS-CoV-2 infection.

Associations of &lt;i&gt;TLR&lt;/i&gt; gene polymorphism with the risk of rheumatic heart disease

Aim of the study was to investigate the associations between TLR gene polymorphism and the risk of rheumatic heart disease (RHD).Material and methods. 251 RHD patients (190 females and 61 males) and 300 healthy donors (190 females and 110 males), whose age was 57 [29; 77] and 53 [21; 80] years (median [lower quartile; upper quartile]), respectively, were recruited in the presented study. Eight polymorphic variants in the TLR gene were genotyped by realtime PCR.Results. We found no statistically significant differences in the frequency of eight polymorphic variants in the TLR1, TLR2, TLR4 and TLR6 genes in the general group of patients. Stratification by gender and age showed that the frequency of the C/C genotype of the TLR1 gene (rs5743551) was increased in females with RHD (11.6 %) compared to the control group (5.3 %); a risk effect was determined for recessive inheritance patterns (odds ratio 2.43, 95 % confidence interval 1.07–5.52, p = 0.029). Moreover, the combination of polymorphic variants TLR2 (rs5743708) – TLR4 (rs4689791) – TLR1 (rs5743551) – TLR2 (rs3804099) showed the greatest significance in RHD risk.Conclusions. Future research on the different populations will allow to discover the general patterns of RHD pathogenesis, which will finally lead to the establishment of therapeutic targets for treatment of streptococcal infection and RHD prevention.

Investigation of the association between the Toll-like receptor 1 rs4833095 variation and gastric adenocarcinoma recurrence.

Toll-like receptors (TLRs) are a family of transmembrane receptors that play key roles in identifying invading pathogens and activating innate immunity. TLR1 has been reported to be associated with the risk of gastric cancer (GC) but that was based on only a simple statistical analysis. We genotyped the TLR1 in 526 GC patients to investigate the association between the variation and gastric cancer survival by the multiplex polymerase chain reaction and sequencing method. The rs4833095 variation (chr4:38798089 [GRCh38. p14], T>C) in the TLR1 gene was genotyped in 526 patients who underwent GC resection. The associations between genotype, survival, and recurrence were investigated. The potential role of TLR1 in stomach cancer was investigated using clinical data from formalin-fixed, paraffin-embedded tissue samples. Patients with the T/C and C/C genotypes of rs4833095 had a lower risk of recurrence than those with the T/T genotype. Recurrence-free periods were substantially longer in patients with the T/C or C/C genotypes (22.6 and 22.3 months, respectively) than in those with the T/T genotype (20.7 months). Patients with the T/C or C/C genotype, low expression levels of VEGF1, high expression levels of ERBB2 and ERCC1, the absence of cancer nodules, a tumor size of less than 5cm, and poor differentiation had a considerably reduced risk of recurrence. TLR1 rs4833095 was correlated with the postresection prognosis of patients with gastric cancer, suggesting that TLR1 may have a role in the onset or progression of gastric cancer.

Effects of toll like receptor 4 (TLR4) and toll like receptor 2 (TLR 2) gene polymorphisms on clinical outcomes in acute non-biliary pancreatitis patients.

In this retrospective study, it was aimed to evaluate effects of Toll Like Receptor 4 (TLR4) and Toll Like Receptor 2 (TLR 2) gene polymorphisms on clinical outcomes in acute non-biliary pancreatitis patients. A total of 108 acute non-biliary pancreatitis patients (ANBP) were retrospectively subjected to the study. Gender, age, number of attacks, hospitalization duration, amylase, lipase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), leukocyte, C-reactive protein (CRP), total bilirubin, direct bilirubin, Atlanta score, ultrasonography (USG), Computer Tomography (CT) and patient outcome differences between TLR 4 Rs4986790, TLR 4 Rs4986791 and TLR 2 groups were evaluated. According to TLR 4 Rs4986790 groups, females were significantly common in AA sequence (AA) group with statistically significant difference (p<0.05). Leukocyte mean of AG sequence (AG) group was significantly higher than of AA group (p<0.05). All parameter differences between TLR 4 Rs4986791 and TLR 2 groups were statistically insignificant (p>0.05). there was a statistically significant correlation between TLR 4 Rs4986790 and gender (r=0.265; p<0.01), Leukocyte (r=0.200; p<0.05) and Pseudocyst (r=0.203; p<0.05). TLR 4 Rs4986790 gene polymorphism had significant effect on leukocyte level in acute non-biliary pancreatitis patients (OR: -0.1.900; p<0.05). Predictive value of leukocyte for TLR 4 Rs4986790 was statistically significant (Area Under Curve: 0.624; p<0.05). For 7.65 leukocyte cut off value, sensitivity for AA gene polymorphism was 84.2% and specificity was 40.5. Although the clinical and outcome parameters of ANBP patients in terms of TLR 4 Rs4986791 and TLR 2 do not show significant differences, research findings point to the diagnostic value of patients' leukocyte parameters in determining TLR-4 Rs4986790 ploimorphism groups.

Insights into the Correlation between Toll-Like Receptor 2 Polymorphism and HBV-Related Disease Progression and Occurrence of Hepatocellular Carcinoma: A Case-Control Study in Egyptian Patients.

In total, 170 chronic HBV patients and 50 healthy controls of comparable age and gender were included in this case-control study. Clinical, laboratory, and imaging evaluations were conducted. ELISA was used to determine serum IL-6 levels, and TLR2 (rs3804099) genotyping allelic discrimination assay was performed using real-time PCR. IL-6 values were significantly higher in the HCC group, followed by the cirrhotic group, than those in chronic hepatitis and control groups (p < 0.001), with a significant correlation with disease activity and progression parameters. TRL2 homozygous TT was the most frequent in the control group, but the CC genotype was significantly more prevalent in the HCC group than that in the other groups. Furthermore, the CC genetic variant was associated with higher levels of IL-6 and viral load in all HBV patients, whereas the TT genotype was associated with larger tumor size. Multivariate regression analysis demonstrated that in chronic HBV patients, viral load and TRL2 polymorphism are independent risk factors associated with the progression from chronic hepatitis to liver cirrhosis and to HCC. Similarly, the HBV viral load (p=0.03, OR = 2.45, and 95% CI: 1.69-3.65), IL-6 levels (p=0.04, OR = 3.45, and 95% CI: 2.01-6.9), and TRL2 variants (p=0.01, OR = 4.25, and 95% CI: 2.14-13.5) are independent risk factors associated with disease progression from cirrhosis to HCC. In chronic HBV patients, TRL2 polymorphism and higher IL-6 levels were positively correlated with a higher likelihood of HCC and chronic hepatitis B disease activity and progression.

The association of TLR4 gene polymorphisms with the severity of peritonitis in acute inflammatory diseases of the abdominal cavity organs.

Aim: To determine the role of TLR4 gene polymorphisms as risk factors for peritonitis severity in patients undergoing surgery for acute inflammatory diseases of the abdominal cavity. Materials and Methods: The study included 139 patients who were operated on for acute abdominal diseases (acute appendicitis and cholecystitis, perforated gastric or duodenal ulcer, etc.). Depending on the number of points on the modified APACHE II scale, patients were divided into two groups: Group 1 - 1-3 points (63 patients, 45.3%) and Group 2 - 4 or more points (76 patients, 54.7%). Polymorphisms rs1927911, rs2149356 and rs4986790 were determined by polymerase chain reaction. Results: The rs1927911 polymorphism of the TLR4 gene was protective for the development of peritonitis (according to the allelic model, OR 0.48; 95% CI 0.27-0.84; p=0.015). Regression analysis revealed a reduced (p=0.015) risk of severe peritonitis in rs1927911 A/A or G/A genotype carriers (OR 0.42; 95% CI 0.21-0.84) compared with G/G genotype carriers. There was no effect on the severity of peritonitis of TLR4 polymorphisms rs2149356 and rs4986790. There was a tendency to increase the frequency of the mutant G rs4986790 allele in patients with severe peritonitis (χ2=2.17; p<0.001). The analysis of the association of TLR4 gene polymorphisms with the phenotype of patients showed that carriers of mutant homozygotes and heterozygotes in the presence of severe peritonitis were older, had a tendency to coagulopathy, higher leukocytosis and leukocyte clotting rate. Conclusions: Thus, the importance of TLR in the development of severe peritonitis was confirmed and the protective role of the rs1927911 promoter polymorphism was established.

The infant gut virome is associated with preschool asthma risk independently of bacteria.

Bacteriophage (also known as phage) communities that inhabit the gut have a major effect on the structure and functioning of bacterial populations, but their roles and association with health and disease in early life remain unknown. Here, we analyze the gut virome of 647 children aged 1 year from the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort, all deeply phenotyped from birth and with longitudinally assessed asthma diagnoses. Specific temperate gut phage taxa were found to be associated with later development of asthma. In particular, the joint abundances of 19 caudoviral families were found to significantly contribute to this association. Combining the asthma-associated virome and bacteriome signatures had additive effects on asthma risk, implying an independent virome-asthma association. Moreover, the virome-associated asthma risk was modulated by the host TLR9 rs187084 gene variant, suggesting a direct interaction between phages and the host immune system. Further studies will elucidate whether phages, alongside bacteria and host genetics, can be used as preclinical biomarkers for asthma.

Common variants in toll-like receptor family genes and risk of gastric cancer: a systematic review and meta-analysis

Background: An increasing number of studies have suggested the relationship between single-nucleotide polymorphisms (SNPs) in toll-like receptor (TLR) genes and gastric cancer (GC) susceptibility; however, the available evidence is contradictory. This meta-analysis aimed to comprehensively evaluate whether the SNPs within the TLR family are related to GC development.Methods: PubMed, Scopus, and China National Knowledge Infrastructure (CNKI) were systematically searched up to May 2023 to obtain the pertinent publications. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were applied to examine the associations using the random-effects model.Results: A total of 45 studies with 25,831 participants (cases: 11,308; controls: 14,523) examining the relation of 18 different SNPs in the TLR family to GC were analyzed. Variations in TLR-4 rs4986790, TLR-4 rs4986791, TLR-5 rs5744174, and TLR-9 rs187084 were significantly associated with increased risk of GC in different genetic models. No significant association was detected for TLR-2-196 to -174de (Delta22), TLR-2 rs3804100, TLR-4 rs11536889, TLR-4 rs11536878, TLR-4 rs2770150, TLR-4 rs10116253, TLR-4 rs1927911, TLR-4 rs10983755, TLR-4 rs10759932, TLR-4 rs1927914, and TLR-10 rs10004195.Conclusion: These findings indicate that variations in TLR-4, TLR-5, and TLR-9 genes were found to be potential risk factors for GC.

Meta-analysis of the association between toll-like receptor gene polymorphisms and hepatitis C virus infection.

The objective of this study is to investigate the association between toll-like receptor (TLR) 3/7 gene polymorphisms and the infection by hepatitis C virus (HCV). PubMed, Embase, Web of Science, Scopus, CNKI, Wanfang Data, and SinoMed were searched to identify studies focusing on the association between the TLR3 rs3775290 or the TLR7 rs179008 single nucleotide polymorphisms (SNPs) and the HCV infection. All the related articles were collected from the inception of each database to 15 January 2023. Our meta-analysis was conducted using the allelic model, the dominant model, and the recessive model. Outcomes were presented by odds ratio (ORs) and 95% confidence interval (95%CI). The heterogeneity across studies was assessed by the I2 test. A subgroup analysis was performed to explore the source of heterogeneity. Funnel plots were drawn to assess the risk of publication bias. Review Manager 5.4 was used for statistical analysis. Ten articles were finally included, among which six studies were analyzed for rs3775290 and five studies were analyzed for rs179008. Studies relating to rs3775290 included 801 patients and 1,045 controls, whereas studies relating to rs179008 included 924 patients and 784 controls. The results of the meta-analysis showed that there is no significant association between rs3775290 gene polymorphism and HCV infection (T vs. C: OR = 1.12, 95%CI 0.97-1.30; TT+CT vs. CC: OR = 1.20, 95%CI 0.73-1.96; TT vs. CT+CC: OR = 1.13, 95%CI 0.68-1.89). The recessive model showed that rs179008-T allele homozygotes had an 89% increased risk of infection by HCV compared with rs179008-A allele carriers (TT vs. AT+AA: OR = 1.89, 95%CI 1.13-3.16). The results of the subgroup analysis demonstrated that the characteristics of the control population may serve as an important source of heterogeneity. In the African populations, individuals with homozygous rs179008-T alleles had a higher risk of infection by HCV than rs179008-A allele carriers (OR = 2.14, 95%CI 1.18-3.87). We did not find that this difference existed in the European populations (OR = 1.24, 95%CI 0.43-3.56). There is no significant association between rs3775290 single nucleotide polymorphism and the infection by HCV. Individuals with homozygous rs179008-T alleles have a higher risk of an infection by HCV than rs179008-A allele carriers, which is statistically significant in the African populations.

Immunogenetic polymorphisms predict therapeutic efficacy and survival outcomes in tumor patients receiving PD-1/PD-L1 blockade.

While immune checkpoint inhibitors (ICIs) demonstrate remarkable clinical responses, only a small subset of patients obtains benefits. Genes linked to the tumor immune system are confirmed to be critical for the treatment of ICIs, and their polymorphisms can contribute to ICI efficacy. Here, we examined the potential of immunogenetic variations to predict the efficacy and survival of the PD-1/PD-L1 blockade. Cancerous patients receiving PD-1/PD-L1 blockade were recruited and followed up. Pivotal genes related to tumor-immunity were filtered through a protein-protein interaction network and the degree algorithm in Cytoscape. Finally, 39 genetic variants were genotyped through multiplex genotyping assays. Association analyses between variants and ICI efficacy and progression-free survival (PFS) were performed. Overall, 318 patients were ultimately enrolled. Hence, three immunogenetic variants were identified as predictors of PD-1/PD-L1 blockade response. Mutant alleles from ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911 were all at increased risk of tumor progression following ICI therapy (OR: 1.475, 1.641, 1.462, respectively; P value: 0.028, 0.017, 0.027, respectively). Significant immunogenetic variants also attained similar trends in the PD-1 blockade, lung cancer, or lung cancer using PD-1 blockade subgroups. Furthermore, the mutant genotypes of CD274 rs2297136 (GG as the reference: HR: 0.50 (95%CI: 0.29-0.88), P value: 0.015) and TLR4 rs1927911 (AA as the reference: HR: 0.65 (95%CI: 0.47-0.91), P value: 0.012) indicated poorer PFS and were both independent prognostic factors. Immunogenetic polymorphisms, including ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911, were first identified as potential predictors of response to PD-1/PD-L1 blockade in tumor patients.

Investigation of the impact of AXL, TLR3, and STAT2 in congenital Zika syndrome through genetic polymorphisms and protein-protein interaction network analyses.

Zika virus (ZIKV) is a human teratogen that causes congenital Zika syndrome (CZS). AXL, TLR3, and STAT2 are proteins involved in the ZIKV's entry into cells (AXL) and host's immune response (TLR3 and STAT2). In this study, we evaluated the role of genetic polymorphisms in these three genes as risk factors to CZS, and highlighted which proteins that interact with them could be important for ZIKV infection and teratogenesis. We evaluate eighty-eight children exposed to ZIKV during the pregnancy, 40 with CZS and 48 without congenital anomalies. The evaluated polymorphisms in AXL (rs1051008), TLR3 (rs3775291), and STAT2 (rs2066811) were genotyped using TaqMan® Genotyping Assays. A protein-protein interaction network was created in STRING database and analyzed in Cytoscape software. We did not find any statistical significant association among the polymorphisms and the occurrence of CZS. Through the analyses of the network composed by AXL, TLR3, STAT2 and their interactions targets, we found that EGFR and SRC could be important proteins for the ZIKV infection and its teratogenesis. In summary, our results demonstrated that the evaluated polymorphisms do not seem to represent risk factors for CZS; however, EGFR and SRC appear to be important proteins that should be investigated in future studies.

Evaluatin of Association of rs4986790 and rs4986791 Single-Nucleotide Polymorphisms in TLR4 with Febrile Neutropenia in Childhood Acute Lymphoblastic Leukemia

Background: Infections cause significant complications and, in severe cases, death in patients with childhood Acute Lymphoid Leukemia (ALL). Toll-like receptors (TLRs) play a crucial role in initiating innate immune responses. Previous studies indicate the role of TLR4 gene polymorphisms in the increased risk of infection in adults and children. This study investigated the potential association between Asp299Gly (rs4986790) and Thr399Ile (rs4986791) polymorphisms in the TLR4 gene with febrile neutropenia, as a hallmark of infection, in children with ALL.&#x0D; Material and Methods: This cross-sectional study was performed on 51 ALL child patients, with age (mean±s.d.) 5.2 ± 3.4 years. Genotype analysis of rs4986790 and rs4986791 polymorphisms in the TLR4 gene was evaluated by ARMS- PCR and PCR-RFLP, respectively. Statistical analysis was performed using SPSS software. P-values &lt;0.05 were considered significant.&#x0D; Results: The rs4986790 and rs4986791 polymorphisms were detected in 5.8% and 7.8% of ALL patients, respectively. The mean of recurrence of febrile neutropenia in patients without TLR4 rs4986790 and TLR4 rs4986791 polymorphisms was 3.1 ±2 and 3 ±1.9, respectively, while in patients with TLR4 rs4986790 and TLR4 rs4986791 polymorphisms, they were 4.6 ± 3 and 5.2 ±2.8, respectively (P = 0.09). No association was found between TLR4 rs4986790 and rs4986791 polymorphisms and the number of febrile neutropenia recurrences (P = 0.4).&#x0D; Conclusion: Although rs4986790 and rs4986791 polymorphisms were detected in ALL patients, these polymorphisms were not associated with febrile neutropenia. It is suggested to investigate other polymorphisms in immune system-related genes and their role in febrile neutropenia.

Association between TLR2, TLR4, and TLR5 genetic variants and the risk of hepatocellular carcinoma in Moroccan population

Hepatocellular carcinoma (HCC) is the fifth most common human malignancy and the fourth most frequent cause of cancer-related deaths worldwide. Toll-like receptors (TLRs), are known to play a key role in hepatocarcinogenesis through induction of inflammation. We aimed to investigate the association between TLR2 rs3804099, TLR4 rs4986790, rs4986791, and rs11536889 and TLR5 rs5744174 and HCC risk in a total of 306 Moroccan subjects, including 152 HCC patient and 154 controls using a TaqMan allelic discrimination assay. Our result showed that the frequency of TLR4 rs11536889 C allele was higher in control group than in HCC patients (OR = 0.52, 95% CI = 0.30-0.88, p = 0.01). Moreover, under the dominant model, we observed that CG/CC genotypes were protective factors against HCC risk (OR = 0.51, 95% CI = 0.28-0.91, p = 0.02). However, no significant differences were found in the allele and genotype frequencies of TLR4 rs4986790 and rs4986791, between HCC patients and controls. Similarly, genotypic frequencies of TLR2 and TLR5 polymorphisms did not differ significantly between HCC patients and controls. However, TLR4 haplotype analysis revealed that ACC haplotype may be protective of HCC risk in patients with HCC (OR = 0.53, 95% CI = 0.31-0.92, p = 0.02). In conclusion, our result suggest that TLR4 rs11536889 polymorphism and ACC haplotype may decrease risk of hepatocellular carcinoma in Moroccan population

Association of single nucleotide polymorphisms of &lt;i&gt;TLR2&lt;/i&gt;, &lt;i&gt;TLR4&lt;/i&gt; and &lt;i&gt;TLR9&lt;/i&gt; with atopic dermatitis

Toll-like receptors (TLRs) are the most studied among all Pattern Recognition Receptors, the main function of which is to initiate innate immune response by recognizing pathogen-associated molecular patterns of various microorganisms on the skin surface. TLR-mediated recognition plays an important role in linking innate and adaptive immunity that ultimately leads to the production of key cytokines, chemokines and antimicrobial peptides. Today, there is growing interest in research on single nucleotide polymorphisms (SNPs) in TLR genes and its influence on susceptibility to inflammatory disease, including atopic dermatitis. The aim of the research was to study the association of the rs5743708 gene polymorphism in the TLR2 gene, the rs4986791 gene polymorphism in the TLR4 gene and the rs352140 gene polymorphism in the TLR9 gene with the risk of developing severe cases of AD. A total of 100 patients with AD were included in the study (38 male and 62 female). The age range was from 18 to 65 years old. All participants were divided into 2 groups according to the SCORAD index (SCORing Atopic Dermatitis). The control group included 72 volunteers over 18 years old. The results of our study showed a statistically significant difference between the moderate AD group and healthy controls in the rs352140 gene polymorphism in the TLR9 gene (Figure 1). The frequency of the GG genotype of SNP rs352140 in TLR9 was 0.169 in the AD group versus 0.329 in the control group (p &lt; 0.05; OR = 0.42; 95% CI = 0.18-0.97).In conclusion, the results of our study showed that the TLR9 rs352140 gene polymorphism may be linked to an increased risk of atopic dermatitis. Moreover, it was found that the GG genotype of SNP rs352140 in TLR9 can be used as a predictor of the risk of developing moderate AD.

Inflammation and endothelial function-related gene polymorphisms are associated with carotid atherosclerosis-A study of community population in Southwest China.

To investigate the relationships between 18 single nucleotide polymorphisms with carotid atherosclerosis and whether interactions among these genes were associated with an increased risk of carotid atherosclerosis. Face-to-face surveys were conducted with individuals aged 40 or older in eight communities. A total of 2377 individuals were included in the study. Ultrasound was used to detect carotid atherosclerosis in the included population. 18 loci of 10 genes associated with inflammation and endothelial function were detected. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). Among the 2377 subjects, 445 (18.7%) subjects had increased intima-media thickness in the common carotid artery (CCA-IMT), and 398 (16.7%) subjects were detected with vulnerable plaque. In addition, NOS2A rs2297518 polymorphism was associated with increased CCA-IMT, IL1A rs1609682, and HABP2 rs7923349 polymorphisms were associated with vulnerable plaque. Besides, GMDR analysis showed significant gene-gene interactions among TNFSF4 rs1234313, IL1A rs1609682, TLR4 rs1927911, ITGA2 rs1991013, NOS2A rs2297518, IL6R rs4845625, ITGA2 rs4865756, HABP2 rs7923349, NOS2A rs8081248, HABP2 rs932650. The prevalences of increased CCA-IMT and vulnerable plaque were high in Southwestern China's high-risk stroke population. Furthermore, inflammation and endothelial function-related gene polymorphisms were associated with carotid atherosclerosis.

Association of Toll-like receptor 2 rs111200466 polymorphism with low serum levels of IL-33 in early childhood.

TLR2 is one of ten human TLRs which plays an important role in the recognition of pathogens and activation of the innate immunity via NF-κB pathway. NF-κB activation induces the expression of various pro-inflammatory genes. This study examines the effect of TLR2 polymorphisms on the production of blood pro-inflammatory cytokines in healthy Finnish children. One hundred forty-six children who participated in a prospective observational birth cohort study in Turku, Finland, were included. DNA samples were analysed by PCR-based sequencing for two common TLR2 polymorphisms (rs5743708 Arg753Gln; rs111200466 -196 to -174del). Serum concentrations of IL-33, IL-31, IL-17A and IL-17F were measured by multiplex immunoassay and sST2 by ELISA in children at the age of 13 months. Children with variant type of TLR2 rs111200466 (ins/del or del/del) had significantly lower level of serum IL-33 (median, 0.00 pg/mL; IQR 0.00 - 17.60) than those with ins/ins type of TLR2 (19.81 pg/mL; IQR 0.00 - 51.78) (P = 0.0001). Almost all study subjects had serum concentrations of IL-17A, IL-17F and IL-31 below the detection limit and therefore not included into the final analyses. No differences in levels of above four cytokines and sST2 were found between TLR2 rs5743708 genotypes (GG and GA). Our results indicated that the TLR2 rs111200466 deletion was associated with a low level of serum IL-33, suggesting that the polymorphism may impair the production of IL-33.

Association of Toll-like Receptors 1, 2, 4, 6, 8, 9 and 10 Genes Polymorphisms and Susceptibility to Pulmonary Tuberculosis in Sudanese Patients.

Genetic factors are important contributors to the development of a wide range of complex disease. Polymorphisms in genes encoding for toll-like receptors (TLRs) usually influence the efficiency of the immune response to infection and are associated with disease susceptibility and progression. Therefore, we aim to describe the first association between TLR1, TLR2, TLR4 TLR6, TLR8, TLR9 and TLR10 genes polymorphisms and susceptibility to pulmonary tuberculosis (PTB) in Sudanese patients. Here we performed a case study which included 160 tuberculosis patients and 220 healthy matched controls from Sudan. In the study population, we evaluated the possible association between 86 markers in TLR1, TLR2, TLR4 TLR6, TLR8, TLR9 and TLR10 genes polymorphisms and susceptibility to PTB disease in Sudanese population using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). From our results it appeared that in the PTB population the TLR1 (rs5743557, rs4833095, rs5743596), TLR2 (rs5743704, rs5743708, rs3804099), TLR4 (rs4986790, rs4986791), TLR6 (rs5743810), TLR8 (rs3764879, rs3764880), TLR9 (rs352165, rs352167, rs187084) and TLR10 (rs4129009) were significantly more often encountered (p<0.0001) than in the control population and were associated with PTB in the Sudanese population. For the other polymorphisms tested, no association with PTB was found in the population tested. The work describes novel mutations in TLR1, TLR2, TLR4, TLR6, TLR8, TLR9 and TLR10 genes and their association with PTB infection in Sudanese population. These results will enhance our ability to determine the risk of developing the disease by targeting specific TLR pathways to reduce the severity of the disease. Future studies are needed in a larger sample to replicate our findings and understand the mechanism of association of TLR polymorphism in PTB.

Genetic polymorphism of some genes of toll-like receptors in patients with influenza A (H3N2)

Background.Among all infectious diseases that occur in the human population, only acute respiratory viral infections, including influenza, lead to massive outbreaks, often taking on the character of epidemics and pandemics. Polymorphism of cytokine genes can be both a factor of predisposition and resistance to infection, the development of the disease, and a long, complicated course of influenza.&#x0D; Aim.Study of the genetic polymorphism of the genes of toll-like receptorsrs5743708 (Arg753Gln, G2258A),TLR3 rs3775291 (Phe412Leu, C1234T),TLR4 rs4986790 (Asp299Gly, A896G),TLR4 rs4986791 (Thr399Ile, C1196T)in healthy individuals and in patients with influenzaA(H3N2).&#x0D; Material and methods.The study, using the continuous sampling method, included patients with influenzaA (H3N2; 89people) who were treated at the Regional Clinical Infectious Diseases Hospital in Chita during the epidemic seasons of 20162017 and 20172018. The control group consisted of 96practically healthy donors. To analyze the polymorphism of theTLR2 rs5743708 (Arg753Gln, G2258A), TLR3 rs3775291 (Phe412Leu, C1234T), TLR4 rs4986790 (Asp299Gly, A896G),andTLR4 rs4986791 (Thr399Ile, C1196T)genes the method of polymerase chain reaction with electrophoretic detection using standard kits from Scientific and Production Company Litekh (Moscow) was applied.Statistical analysis was carried out in accordance with the principles of the International Committee of Medical Journal Editors and the Statistical Analysis and Methods in the Published Literature recommendations. Pearson's 2test was used for comparative evaluation of qualitative nominal data.&#x0D; Results.Patients with influenzaA (H3N2) more often had heterozygousTLR2 753Arg/Glnvariants [2=8.26, p=0.02; odds ratio (OR) 3.00; 95% confidence interval (CI) 1.336.73], homozygousTLR3 412Leu/Leuvariants (2=11.68, p=0.003; OR=2.39; 95% CI 1.043.61), heterozygous variants ofTLR4 299Asp/Gly(2=6.97; p=0.03; OR=2.15; 95% CI 1.024.70) and399Thr/Ile(2=8.39; p= 0.01; OR=2.30; 95% CI 1.064.88) compared with a group of healthy donors.&#x0D; Conclusion.The genotypes753Arg/Glnof theTLR2gene,412Leu/Leuof theTLR3gene,299Asp/Glyof theTLR4gene,Thr399Ileof theTLR4gene predispose to the development of influenzaA (H3N2); carriage of genotypes753Arg/Argof theTLR2gene,412Phe/Pheof theTLR3gene,299Asp/Aspof theTLR4gene,399Thr/Throf theTLR4gene reduces the likelihood of the influenzaA(H3N2) development.

Potential Impact of Polymorphisms in Toll-like Receptors 2, 3, 4, 7, 9, miR-146a, miR-155, and miR-196a Genes on Osteoarthritis Susceptibility.

Osteoarthritis (OA) is a progressive inflammatory disease of synovial joints and a leading cause of disability among adults. Inflammation-related genes, including genes for Toll-like receptors (TLRs), are tightly controlled by several microRNAs that, in addition to their pivotal role in the epigenetic regulation of target genes, are ligands for TLR activation and downstream signaling. Thus, we evaluated the association between OA risk and genetic variants in TLR2, TLR3, TLR4, TLR7, TLR9, and microRNAs that regulate TLRs signaling miR146a, miR155, and miR196a2. Our study group consisted of 95 surgically treated OA patients and a control group of 104 healthy individuals. Genetic polymorphisms were determined using TaqMan real-time PCR assays (Applied Biosystems). Adjusted logistic regression analysis demonstrated that polymorphisms in TLR4 rs4986790 (OR = 2.964, p = 0.006), TLR4 rs4986791 (OR = 8.766, p = 0.00001), and TLR7 rs385389 (OR = 1.579, p = 0.012) increased OA risk, while miR-196a2 rs11614913 (OR = 0.619, p = 0.034) was significantly associated with decreased OA risk. Our findings indicate that polymorphisms in the TLR4 and TLR7 genes might increase OA risk and suggest a novel association of miR-196a2 polymorphism with decreased OA susceptibility. The modulation of TLRs and miRNAs and their cross-talk might be an attractive target for a personalized approach to OA management.