Search Results (10)

(1) Background: Neonatal sepsis continues to be one of the leading causes of mortality and morbidity, particularly in underdeveloped countries. We aimed to compare laboratory parameters between clinical early-onset sepsis (clinEOS) and NNNon-clinEOS groups and to evaluate the association between TLR2-Arg753Gln, TLR4-Asp299Gly, IL6-174G/C, and IL10-1082G/A gene single-nucleotide polymorphisms and clinical EOS susceptibility in preterm newborns. (2) Materials and Methods: Genotyping of the TLR2, TLR4, IL6, and IL10 polymorphisms was performed in 36 preterm neonates with polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP). Logistic regression analysis was used to test the associations between the studied gene polymorphisms and EOS susceptibility. (3) Results: Statistically significant differences in gestational age and birth weight were observed between the two groups, with preterm neonates with clinical EOS having a lower mean gestational age (mean (SD): 29.4 (2.8) weeks vs. 32.6 (1.1); p = 0.00002) and a lower mean birth weight (1342.1 (446.5) gr. Vs. 1984 (376.9)) than preterm neonates without clinical EOS. C-reactive protein (CRP) values measured on the first day significantly increased in the clinEOS group compared with the non-clinEOS group (median, 95% CI: 0.80 [0.40, 1.15] vs. 0.30 [0.02, 0.50]). The mean number of neutrophils significantly decreased in the preterm neonates with clinical EOS (mean difference: 17.3%; 95% CI: [4.0%, 30.5%]; p = 0.0126) and non-clinEOS group (mean difference: 20.8%; 95% CI: [1.8%, 39.9%]; p = 0.0354) between the first and seventh hospitalization days. In the dominant model, the A/G + A/A variant genotype of the IL10-1082G/A polymorphism significantly increased the odds of clinical EOS compared with the GG genotype (OR = 5.25; p = 0.0322), but the gestational-age-group adjusted model yielded p = 0.0752. (4) Conclusions: The results of the current study suggest that IL10-1082G/A gene polymorphism is a significant risk factor for clinical early-onset sepsis development in preterm neonates, but there was no evidence of a gestational age-group independent direct effect of IL10-1082G/A gene polymorphism on clinical EOS susceptibility. The results should be considered as exploratory. Full article

Alzheimer’s disease (AD) has been studied extensively and is characterized by plaques deposited throughout the brain. Plaques are made of beta-amyloid (Aβ) peptides which have undergone fibrillogenesis to form insoluble Aβ fibrils (fAβ) that are neurotoxic. Receptor for Advanced Glycation End end products (RAGE), toll-like receptors (TLRs) 2 and 4, and co-receptor CD14 recognize negatively charged binding regions on fAβ to activate microglia and release proinflammatory cytokines. In this study, we used two experimentally resolved fAβ structures (type I and II) isolated from AD brain tissue to elucidate binding patterns of fAβ with RAGE, TLR2, TLR4, and CD14 and investigated whether binding was affected by fibril structure or system pH. Receptors TLR2 and RAGE formed tight complexes with both type I and II fibrils, while TLR4 showed selectivity for type I. CD14 binding was less tight and selective for type II. Binding was pH dependent for CD14, TLR4, and RAGE but not TLR2. We explored the effects of familial mutations on fibril structure to determine whether mutants of type I or II structures are feasible. Finally, we investigated whether mutations affected binding interactions of fAβ with proteins. The Arctic (Glu22Gly), Dutch (Glu22Gln), and Iowa (Asp23Asn) mutations showed similar effects on binding affinity. Italian (Glu22Lys) mutations abrogated binding, whereas type I and II fibrils with Flemish (Ala21Gly) mutations were not shown to be feasible. Results highlight the adaptability of immune receptors in recognizing damaging molecules, with fibril structure and pH being the main recognition determinants predicated on disease progression. In silico mutations showed that aggregates similar to type I and II structures were plausible for some familial mutations. Full article

Periodontitis is a multifactorial disease linked to host immune response and genetic predisposition. The TLR4 Asp299Gly single-nucleotide polymorphism (SNP, rs4986790) has been associated with altered responses to bacterial lipopolysaccharide (LPS) and may influence susceptibility to inflammatory diseases. Given the central role of TLR4 in innate immune recognition of periodontal pathogens, this study investigates the role of rs4986790 in modulating susceptibility to periodontal inflammatory destruction. A total of 1410 individuals from four populations were genotyped, with findings indicating a significant protective effect of the polymorphic allele. Functional assays demonstrated enhanced IL-8 secretion and increased sensitivity to CD14 inhibition in cells expressing the variant receptor. These results suggest that rs4986790 modifies the LPS response via TLR4, potentially offering protection against periodontal breakdown. Full article

Several indirect findings suggest that host-related factors influence susceptibility to Coxiella burnetii infection. We decided to explore the influence of genetic factors related to both innate and adaptive immunity in acute Q fever susceptibility. TLR2 (Arg753Gln) and TLR4 (Asp299Gly, Thr399Ile) polymorphisms, along with HLA-DRB1 alleles, were analyzed for 38 patients with acute Q fever, 38 matched controls, and 121 blood donors. No significant associations were found for TLR polymorphisms. However, HLA-DRB1*04 was more frequent in patients. HLA-DRB1 variants may play a role in Q fever susceptibility, supporting the need for further investigation into their potential implications for vaccination and risk assessment. Full article

Polymorphisms in the Toll-like receptor 4 (TLR4) and IL-17 cytokine genes play a role in liver fibrosis progression among patients with MASLD. The current study aimed to investigate whether the IL17 (A7448G and G197A) and TLR4 (Asp299Gly and Thr399Ile) gene polymorphisms are associated with increased liver fibrosis stages in MASLD patients. Genotyping for the IL17F-A7488G, IL17A-G197A, TLR4-Asp299Gly, and TLR4-Thr399Ile polymorphisms was performed on a sample of 42 MASLD patients and 39 healthy controls. Serum levels of IL17F, IL17A, and TLR4 were measured using ELISA techniques. Bivariate analysis revealed significant associations between glycemic levels (p = 0.006), lipid metabolism (total cholesterol, HDL cholesterol, triglycerides), and the severity of liver fibrosis (p < 0.05). The IL17A-G197A GA and AA genotypes were more frequent in patients with advanced liver fibrosis compared to those without fibrosis (GA genotype frequency: 42.9% vs. 7.7%; AA genotype frequency: 14.3% vs. 5.1%; adjusted p = 0.0423). In the multivariable ordinal logistic regression, the IL17A-G197A polymorphism remained significantly associated with higher liver fibrosis stages (adjusted p = 0.0155). Patients with the dominant genotype (GA + AA) of the IL17A-G197A polymorphism exhibited 3.91 times greater odds of experiencing at least a one-stage increase in liver fibrosis compared to those with the GG genotype (adjusted OR = 3.91, 95% CI: 1.33–12.34). This study indicates that IL17-related genetic polymorphisms and metabolic characteristics significantly affect liver fibrosis progression in MASLD patients, with the IL17A-G197A gene polymorphism identified as an independent multivariate predictor of fibrosis progression. Full article

(1) Background: Interleukin 17 (IL17) and toll-like receptor 4 (TLR4) elevate the risk of metabolic and liver diseases. (2) Methods: This study’s objective was to explore the association of IL17 and TLR4 gene polymorphisms with MASLD susceptibility and test their effect on serum IL17 and TLR4 levels. A total of 43 patients with MASLD (MASH/MAFL) and 38 healthy individuals were genotyped for IL17F-A7488G, IL17A-G197A, TLR4-Asp299Gly, and TLR4-Thr399Ile polymorphisms using PCR-RFLP. ELISA methods determined IL17F, IL17A, and TLR4 serum levels. (3) Conclusions: Patients carrying the variant genotypes (A/G + G/G) of IL17-A7448G (OR = 5.25), (G/A + A/A) of IL17-G197A (OR = 10.57), (Asp/Gly + Gly/Gly) of TLR4-Asp299Gly (OR = 3.52), or (Thr/Ile + Ile/Ile) of TLR4-Thr399Ile (OR = 9.87) had significantly increased odds of MASH. Genotype (G/A + A/A) of IL17-G197A was significantly associated with the odds of MAFL (p = 0.0166). Allele A of the IL17-G197A polymorphism was significantly related to increased odds of MAFL (OR = 4.13, p = 0.0133). In contrast, allele A of IL17-G197A (OR = 5.41, p = 0.008), allele Gly of TLR4-Asp299Gly (OR = 3.19, p = 0.046), and allele Ile of TLR4-Thr399Ile (OR = 6.94, p = 0.008) polymorphisms were significantly related to an increased risk of MASH. Allele A of IL17A-G197A, allele Gly of TLR4-Asp299Gly, and allele Ile of TLR4-Thr399Ile gene polymorphisms were significantly associated with the increased odds of MASLD. In patients with MASLD, we found significant influence from the IL17A-G197A gene polymorphism on IL17F levels (p = 0.0343). Full article

Ovarian cancer (OC) is one of the most common cancers threatening women’s lives around the world. Epithelial ovarian tumors represent the most common ovarian neoplasms. Most OC patients are diagnosed at the advanced stage, and there is an urgent need to identify novel biomarkers of the disease. Single-nucleotide polymorphisms (SNPs) in TLR genes may serve as crucial markers of cancer susceptibility. We investigated the frequency of TLR polymorphisms in a group of 200 women, including 70 with OC. Four SNPs, two each in TLR4 (rs4986790 and rs4986791) and TLR9 (rs187084 and rs5743836), were analyzed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). The digested fragments were separated and identified by multicapillary electrophoresis. The load quantification of human papillomavirus (HPV) types 16/18 was determined using a digital droplet PCR method. We found an increased frequency of heterozygous genotype and minor allele of the TLR4 rs4986790 SNP in women with OC compared with healthy controls, and this result remained highly significant after Bonferroni’s correction for multiple testing (p < 0.0001). No evidence of linkage disequilibrium was found with any of the examined TLR SNPs. The findings suggest that the TLR4 Asp299Gly polymorphism could be a genetic risk factor for the development of OC. Full article

Toll-like receptors (TLR) play an eminent role in the regulation of immune responses to invading pathogens during sepsis. TLR genetic variants might influence individual susceptibility to developing sepsis. The current study aimed to investigate the association of genetic polymorphisms of the TLR2 and TLR4 with the risk of developing sepsis with both a pilot study and in silico tools. Different in silico tools were used to predict the impact of our SNPs on protein structure, stability, and function. Furthermore, in our prospective study, all patients matching the inclusion criteria in the intensive care units (ICU) were included and followed up, and DNA samples were genotyped using real-time polymerase chain reaction (RT-PCR) technology. There was a significant association between TLR2 Arg753Gln polymorphisms and sepsis under the over-dominant model (p = 0.043). In contrast, we did not find a significant difference with the TLR4 Asp299Gly polymorphism with sepsis. However, there was a significant association between TLR4 Asp299Gly polymorphisms and Acinetobacter baumannii infection which is quite a virulent organism in ICU (p = 0.001) and post-surgical cohorts (p = 0.033). Our results conclude that the TLR2 genotype may be a risk factor for sepsis in adult patients. Full article

We aimed to explore the role of TLR4 (rs4986790) polymorphism in the nasopharyngeal (NP) bacterial colonization and its consequent impact on the development of childhood asthma. A semi-quantitative culture of NP swabs was performed on 473 children at 2 months of age and on 213 children at 13 months of age. TLR4 polymorphism was analyzed for 396 children. Children were followed from birth to the age of 7.5 years and the final outcome was physician-diagnosed asthma. The associations between TLR4 genotype, bacterial colonization, and asthma were analyzed. Children with TLR4 AG or GG genotype were more often colonized with Moraxella catarrhalis at 2 months of age (p = 0.009) and Haemophilus influenzae at 13 months of age (p = 0.018). Children who were colonized with H. influenzae at 13 months of age had a significantly higher risk of later development of asthma (p = 0.004). M. catarrhalis or H. Influenzae colonization at 2 months of age or TLR4 genotype Asp299Gly were not associated with the development of childhood asthma. TLR4 Asp299Gly polymorphism was associated with an increased risk of colonization of M. catarrhalis and H. influenzae in children. The colonization with H. influenzae at 13 months of age was associated with a higher risk of later development of childhood asthma. Full article

Background: Inflammatory mechanisms are key to the pathogenesis of atherosclerosis. Functional polymorphisms of TLR-4, Asp299Gly and Thr399Ile, CD14 promoter area C260T polymorphism and plasma levels of soluble CD14 are studied in subjects with Coronary Artery Disease (CAD). Methods: DNA was obtained from 100 human paraffin-embedded aortic specimens, from cadavers with known coronary atheromatosis (Group A) and 100 blood samples from patients with CAD, as detected by cardiac Multi-Detector-row-Computed-Tomography (MDCT) (Group B). Our control group consisted of 100 healthy individuals (Group C). Genotyping was performed by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction (RFLP-PCR). Plasma levels of sCD14 were measured with ELISA. Results: For TLR-4 Asp299Gly and Thr399Ile polymorphisms, no statistically significant differences were observed. Regarding the C260T polymorphism, frequencies of T allele were significantly higher in the control group compared to the case group (p = 0.05). The Odds Ratio (OR) showed statistically significant association of TT genotype with healthy individuals (OR 0.25, 95% Confidence Interval CI 0.10–0.62, p = 0.0017). Plasma levels of sCD14 in patients with CAD (mean value = 1.35 μg/mL) were reduced when compared to reference value. Conclusions: The studied polymorphisms ofTLR-4 showed no association with CAD. Conversely, the functional polymorphism of CD14 has a statistically significant difference in expression between healthy and affected by CAD individuals. Full article