Asp299Gly Gene Polymorphisms Research Articles

Association between SNP rs4986790 and COVID-19 infection severity among Baghdad patients

Introduction and Aim: COVID-19, an infectious disease caused by the SARS-CoV-2 coronavirus, is distinguished by the manifestation of severe acute respiratory syndrome. Toll-like receptors (TLRs) are signaling molecules that play crucial roles in the innate immune system through their recognition of pathogen-associated molecular patterns in diverse microorganisms, including coronaviruses. The primary aim of this research was to investigate the plausible association between the TLR4 gene Asp299Gly polymorphism and the degree of infection severity among individuals who contracted COVID-19 in Baghdad, Iraq. Materials and Methods: This cross-sectional prospective study was carried out in Baghdad to investigate the Asp299Gly polymorphism within the TLR4 gene in a cohort of 90 patients diagnosed with Covid-19. Out of the total number of patients, 45 individuals exhibited symptoms indicative of a moderate infection, while the remaining 45 patients presented with a severe illness. The Asp299Gly polymorphism was analyzed using polymerase chain reaction (PCR) technique and restriction fragment length polymorphism (RFLP). Results: Genotyping for the Asp299Gly polymorphism showed only one among the 90 (1.1%) Covid-19 patients tested to be positive. No significant association was seen between covid-19 severity and Asp299Gly (P = 0·31) polymorphism. Conclusion: Our study found no association between SNP rs4986790 of TLR4 gene and COVID-19 severity among Covid-19 patients in Baghdad city.

The role of Toll-like receptor 4 gene polymorphism in the development of organ dysfunction in patients with severe pneumonia associated with A/H1N1 influenza

The aim of the study. To identify the frequency of occurrence of TLR4 Asp299Gly (rs4986790) gene polymorphism and to establish its contribution to the development of organ dysfunction in patients with severe pneumonia associated with A/H1N1 influenza.Materials and methods. The study included 55 patients with severe pneumonia associated with A/H1N1 influenza. Inclusion criteria: severe pneumonia; consolidation/ground-glass syndrome according to chest X-ray/CT. Exclusion criteria: unstable hemodynamics; body mass index > 30; diabetes mellitus; HIV; tuberculosis, oncopathology. Verification of the pathogen in the respiratory swab was carried out using PCR method: A/H1N1 influenza virus RNA was identified. The age of the patients was 47 [38; 62] years. Among all the patients the proportion of men was 47.8 %, of women – 52.2 %. Patients were divided into 2 groups: group 1 included patients with SOFA scale (Sequential Organ Failure Assessment) score ≥ 2 points; group 2 – patients with SOFA scale score ˂ 2 points. Gene SNPs were determined by PCR method using standard kits developed by Research and Production Company “Litekh” (Moscow). Amplification of the TLR4 gene fragments was carried out in a thermocycler Bis-M111 (Bis-N LLC, Novosibirsk). Genomic DNA isolated from whole blood leukocytes using the “DNA Express Blood” reagent was analyzed followed by an amplification reaction. The amplification product was detected in a 3% agarose gel.Results. Multiple organ dysfunction (SOFA scale score ≥ 2 points) in patients with severe pneumonia associated with A/H1N1 influenza was registered in 24 (43.6 %) cases. When analyzing the frequency of occurrence of the minor Gly allele, according to genetic models, the differences were established between patients of the groups 1 and 2 in codominant (p = 0.023; odds ratio (OR) – 8.82 (0.95–81.89)) and dominant (p = 0.005; OR = 12.35 (1.40–109.07)) models.Conclusion. Severe pneumonia associated with A/H1N1 influenza is accompanied by a high incidence of organ dysfunction. The risk of organ failure development is 2.1 times increased in patients with severe pneumonia with identified TLR4 Asp299Gly gene polymorphism, which probably requires further study.

TOLL LIKE RECEPTOR TYPE FOUR GENE POLYMORPHISM IN NEONATAL SEPSIS IN ZAGAZIG UNIVERSITY CHILDREN’S HOSPITAL

Introduction: The immune response constitutes the first-line defense against microbial infections. Toll like receptors (TLRs) play a fundamental role in neonatal innate immunity, and one of them, toll like receptor 4 (TLR4) is considered a major pattern recognition receptor (PRR) in recognizing lipopolysaccharide (LPS) of gram-negative bacteria. Single nucleotide polymorphisms (SNPs) among various TLR genes have been identified and maybe related to susceptibility/resistance to certain infections and other inflammatory diseases.Objective: The purpose of this study was to find a relation between sepsis-related outcomes in neonates and TLR4 Asp299Gly gene polymorphism.Method: we carried out a case control study on 72 neonates. 36 neonates with culture proven gram-negative sepsis and 36 neonates as controls. Both groups were genotyped for TLR4 Asp299Gly gene polymorphism, by polymerase chain reaction (PCR), and restriction fragment length polymorphism analysis (RFLP) by using BccI enzyme.Results: No statistically significant association between TLR4 Asp299Gly gene polymorphism and severity of neonatal sepsis (P>.99).Conclusion: TLR4 Asp299Gly gene polymorphism is not associated with increased severity of gram-negative bacterial sepsis in neonates.

Toll-like receptor 4 gene Asp299Gly and Thr399Ile polymorphisms in type 2 diabetes mellitus: A meta-analysis of 15,059 subjects

AimsToll-like receptor 4 (TLR4) gene Asp299Gly and Thr399Ile polymorphisms have been reported to be associated with susceptibility to type 2 diabetes mellitus (T2DM) with inconsistent results. In an effort to clarify earlier inconclusive results, a meta-analysis evaluating the precise associations between TLR4 gene Asp299Gly and Thr399Ile polymorphisms and T2DM risk was performed. MethodsWe searched the PubMed, Embase, Web of Science, CBMdisc, CNKI, and Google Scholar until July 17, 2014. Additionally, hand searching of the references of identified articles were performed. Original observational studies dealing with the associations between TLR4 gene Asp299Gly and Thr399Ile polymorphisms and T2DM risk were selected. Heterogeneity and publication bias were determined and the meta-analysis was performed by Review Manager 5.1.4 and Stata 11.0. ResultsSeventeen articles involving 25 studies were included in the final meta-analysis, covering a total of 5963 T2DM cases and 9096 controls. For TLR4 gene Asp299Gly polymorphism, 17 studies were combined showing no evidence for association between TLR4 gene Asp299Gly polymorphism and T2DM risk. For TLR4 gene Thr399Ile polymorphism, eight studies were combined. There was also lack of evidence for significant association between TLR4 gene Thr399Ile polymorphism and T2DM risk. In addition, the similar results were obtained in the sensitivity analyses. ConclusionsThe present meta-analysis indicates that TLR4 gene Asp299Gly and Thr399Ile polymorphisms are not associated with increased T2DM risk.

Toll-like receptor 4 gene Asp299Gly polymorphism in myocardial infarction: A meta-analysis of 15,148 subjects

It remains controversial regarding the association between toll-like receptor 4 (TLR4) gene Asp299Gly (+896 A/G) polymorphism and myocardial infarction (MI) risk. Thus, a large-scale meta-analysis evaluating the potential association between this gene variant and MI risk is required. PubMed, Embase, Web of Science, CBMdisc, CNKI, and Google Scholar were searched until February 6, 2013. All the statistical tests were performed using Stata 11.0. Nine articles involving 10 studies were included in the final meta-analysis, covering a total of 8299 MI cases and 6849 controls. Overall, no significant association was found between the TLR4 gene Asp299Gly polymorphism and MI risk (G allele vs. A allele: OR=0.95, 95% CI=0.74–1.22, p=0.71; G/G vs. A/A: OR=1.03, 95% CI=0.54–1.98, p=0.93; G/G vs. A/G+A/A: OR=1.05, 95% CI=0.55–2.03, p=0.87; G/G+A/G vs. A/A: OR=0.92, 95% CI=0.75–1.13, p=0.42). In the subgroup analysis based on source of controls, there was also lack of evidence for significant association between the TLR4 gene Asp299Gly polymorphism and MI risk. In summary, the present meta-analysis indicated that the TLR4 gene Asp299Gly polymorphism was not associated with MI risk.

Genetic Polymorphism of Toll-like Receptor 4 — Predictor of Susceptibility to Recurrent Course of Chronic Pyelonephritis in Children

Objective of investigation: to study the role of Toll-like receptor 4 Asp299Gly gene polymorphism in the implementation of susceptibility to chronic pyelonephritis, to analyze its association with the major manifestations of the disease and to assess the impact on the synthesis of interleukin-6 in the blood of sick children.Methods. We examined a group of children aged 1–15 years with chronic pyelonephritis in the active stage (n = 60). Control group consisted of 95 apparently healthy people. Results. There were revealed significantly higher prevalence of Toll-like receptor 4 Asp299Gly gene polymorphism among children with chronic pyelonephritis (n = 60), identified a statistically significant correlation of mutant genotypes Asp299Gly, Gly299Gly with manifestation of the disease before the age of 3, and frequent episodes of acute respiratory viral infections, torpid urinary syndrome, unstable remission and increased secretion of interleukin-6 (p < 0.001). Thus, genetically determined Toll-like receptor 4 Asp299Gly gene polymorphism is a marker of high risk of early manifestation of chronic inflammation in the kidney interstitium and prolonged recurrent clinical course of the disease in children.

Toll-like receptor 4 gene Asp299Gly polymorphism in ischemic cerebrovascular disease: a meta-analysis

Epidemiological studies have evaluated the association between Toll-like receptor 4 (TLR4) gene Asp299Gly (rs4986790) polymorphism and the risk of ischemic cerebrovascular disease, but the results are inconsistent. In an effort to clarify earlier inconclusive results, a meta-analysis was performed. We searched the PubMed, Web of Science, Embase, Cochrane database, Clinicaltrials.gov, Current Controlled Trials, CNKI, CBMdisc, Chinese Clinical Trial Registry and Google Scholar until up to 20 July 2013. Additionally, hand searching of the references of identified articles was performed. Original observational studies investigating the association between TLR4 gene Asp299Gly polymorphism and ischemic cerebrovascular disease risk were included. All statistical analyses were performed using Stata 11.0. The search strategy identified 1038 potentially relevant articles, seven of which were included in the final meta-analysis, covering a total of 1767 cases and 2785 controls. Overall, no significant association was found between TLR4 gene Asp299Gly polymorphism and ischemic cerebrovascular disease risk (for G allele versus A allele: OR = 0.95, 95% CI = 0.75–1.21, p = 0.69; for G/G+A/G versus A/A: OR = 0.96, 95% CI = 0.75–1.22, p = 0.73). In addition, the similar results were obtained in the sensitivity analysis based on studies with the high quality. In summary, the present meta-analysis indicates that TLR4 gene Asp299Gly polymorphism is not associated with increased ischemic cerebrovascular disease risk.

TLR2 and TLR4 gene polymorphisms in Turkish vitiligo patients

It has been shown that toll like receptors (TLR) may be involved in some inflammatory skin diseases such as psoriasis, atopic dermatitis. Vitiligo is an acquired pigmentation disorder of unknown aetiology. A number of genes playing a role in inflammatory response may be associated with development of vitiligo. To investigate whether there is an association between TLR 2 and TLR4 gene polymorphisms in Turkish patients with vitiligo. A total of 100 patients (59 women and 41 men) with vitiligo and 100 controls (58 women and 42 men) were included in the study. The TLR2 gene Arg753Gln and TLR4 gene Asp299Gly and Thr399Ile polymorphisms were genotyped by using polymerase chain reaction and restriction fragment length polymorphism method. The data were analysed by Mann-Whitney U-test, chi-squared test and logistic regression analysis. Significant difference was found in the distribution of TLR2 Arg753Gln genotype and in the allele frequencies TLR2 753Gln between vitiligo patients and healthy subjects (P < 0.05). The distribution of TLR4 Asp299Gly genotype was significantly higher in the patient group (10%) than in the control group (%2) (P < 0.05). The TLR4 Thr399Ile distribution did not show any difference in both vitiligo and healthy groups. Our findings suggest that Toll-like receptor 2 gene Arg753Gln and Toll-like receptor 4 Asp299Gly gene polymorphisms are associated with vitiligo susceptibility in Turkish patients.

Analysis of association between TLR-4 Asp299Gly and Thr399Ile gene polymorphisms and chronic periodontitis in a sample of south Indian population

Background:To analyze the association between TLR-4 Asp299Gly and Thr399Ile gene polymorphisms and chronic periodontitis in a sample of south Indian population.Materials and Methods:Genomic DNA was obtained from peripheral blood of 60 patients with chronic periodontitis and 60 periodontally healthy subjects. TLR-4 Asp299Gly and Thr399Ile gene polymorphisms were genotyped by a polymerase chain reaction–restriction fragment length polymorphism method. The data were analyzed by a χ2-test and by relative risk estimation.Results:Thr399Ile alleles were found in 4% of chronic periodontitis patients and in 1% of periodontally healthy subjects. The prevalence of a Thr399Ile heterozygote was found to be 5% in the chronic periodontitis group and 1.67% in the periodontally healthy group, respectively. Homozygosity for TLR-4 Thr399Ile was seen in chronic periodontitis patients only, which was 1.67%. The TLR-4 Asp299Gly gene polymorphism was not detected in either chronic periodontitis or periodontally healthy groups.Conclusion:There is no significant association between TLR-4 Thr399Ile polymorphism and chronic periodontitis in a sample of south Indian population.

Toll-like receptor 4 gene (Asp299Gly) polymorphism associates with carotid artery elasticity: The cardiovascular risk in young Finns study

Objective Early subclinical markers of atherosclerosis, such as carotid artery intima media thickness (IMT) and elasticity predict future coronary events. The G allele of the Toll-like receptor 4 (TLR-4) gene Asp299Gly polymorphism has been previously associated with decreased development of atherosclerosis and with lower risk of myocardial infractions. We wanted to examine the association of this polymorphism with carotid IMT and compliance in a population of young Finnish Caucasian adults. Methods Carotid artery IMT and elasticity indices of 2201 study subjects who participated in a randomized multicenter study (cardiovascular risk in young Finns study) were measured with ultrasound. The genotyping was performed using the TaqMan 5′-nuclease assay. Results According to multivariate linear regression analysis adjusted with potential confounders, the G allele carriers had significantly higher carotid arterial compliance, measured in increase of luminal diameter percentage in response to blood pressure rise of 10 mmHg, than did the AA homozygotes ( β = 0.099 with 95% CI 0.029–0.169 and p = 0.006). The difference between AA homozygotes and GG homozygotes was even more pronounced ( β = 0.382 with 95% CI 0.119–0.644 and p = 0.004). Variation in the TLR-4 genotype was not related with IMT. The results of the two independent study cohorts of Eastern and Western Finland were in accordance with the results of the whole combined study population. Conclusion The G allele of the TLR-4 gene Asp299Gly polymorphism is associated with increased carotid artery compliance in young adults. This beneficial effect of the G allele may reduce the risk of future cardiovascular events.

Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction

Variation in the gene encoding toll-like receptor 4 (TLR4), a transmembrane receptor that mediates inflammatory responses to bacterial endotoxin, has been associated with susceptibility to atherosclerosis and its complications, such as myocardial infarction (MI), the pathogenesis of which involves inflammation. A recent study has also indicated that TLR4 gene variation influences the effect of statin treatment on reducing atherosclerosis complications. We studied the TLR4 gene Asp299Gly polymorphism in relation to susceptibility to myocardial infarction in a cohort of patients with angiographically documented coronary artery disease, and performed a meta-analysis using data sets from three independent studies. The meta-analysis showed that overall, odds ratio (OR) for MI was 0.73 [95% confidence interval (CI) 0.55-0.96, P=0.024] in 299Gly carriers compared to non-carriers, and there was no evidence of heterogeneity among the sample sets (P=0.679). In our patient cohort, a significant association of 299Gly bearing genotypes with lower susceptibility to myocardial infarction was observed only in patients receiving statin treatment, with 299Gly carriers having an OR of 0.49 (95% CI 0.27-0.78, P=0.015) for MI compared to non-carriers. These results are consistent with the notion that variation in the TLR4 gene contributes to inter-individual variability in susceptibility to coronary ischaemic events, and that TLR4 genotype and statin treatment may have a synergistic effect.

Toll–like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes

Background Coronary artery disease (CAD) and, increasingly, diabetes are recognized as having an inflammatory basis. Membrane toll-like receptors (TLRs) activate signaling pathways that up-regulate inflammation. We evaluated whether the Asp299Gly polymorphism in the TLR4 gene, which impairs inflammatory responses, is associated with reduced vascular inflammation (assessed by C-reactive protein [CRP]) and a decreased risk for CAD and diabetes. Methods 1894 patients without acute myocardial infarction undergoing coronary angiography were studied. Genotyping was performed by real-time polymerase chain reaction. CAD was defined as ≥70% stenosis. Diabetes was diagnosed by patients' referring physicians. CRP was measured by fluorescence polarization immunoassay. Regression analyses adjusted for traditional cardiac risk factors. Results Patients averaged 64 ± 11 years of age, and 69% were male. Asp299Gly genotype frequencies were: AA = 0.911 (n = 1725), AG = 0.086 (n = 164), and GG = 0.003 (n = 5), in keeping with Hardy-Weinberg equilibrium. CRP was lower among G-allele carriers (median = 1.11 mg/dL) than wild-type (AA) subjects (1.23 mg/dL, adjusted P = .044). G-allele carriers also had a lower prevalence of CAD (65% vs. 73%, OR = 0.67, CI = 0.46–0.99, adjusted P = .048) and diabetes (11% vs. 18%, OR = 0.63, CI = 0.42–0.95, adjusted P = .029), which persisted in multivariate logistic regression analyses. 299Gly carriage did not affect clinical outcomes nor interact with statin therapy. Conclusions The TLR4 299Gly allele was associated with reduced CRP levels and, in parallel, a decreased risk of angiographic CAD and clinical diabetes. These findings suggest that down-regulation of innate immune responsiveness could beneficially modify CAD and diabetes risk and might provide a novel basis for genetic risk stratification and therapeutic targeting.

Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events.

Atherosclerosis is a chronic inflammatory disease of the blood vessels. Toll-like receptor 4 (TLR4) is a transmembrane receptor that is involved in mediating inflammatory responses to bacterial endotoxin and other ligands. The aim of this study was to search for an association between a common functional polymorphism of TLR4--Asp299Gly--and acute coronary syndrome. We conducted a case-control study of 183 patients with acute coronary syndromes and 216 controls. We screened the TLR4 gene for the Asp299Gly polymorphism using a 5' fluorogenic assay. The 299Gly allele was associated with a decreased risk of acute coronary events independently of standard coronary risk factors. The adjusted odds ratio associated with this allele was 0.41 (95% CI, 0.18 to 0.95; P=0.037). In controls, TLR4 heterozygosity was also associated with a significant decrease in plasma fibrinogen and soluble vascular cellular adhesion molecule-1 levels (P<0.01). These results, which must be confirmed by a prospective longitudinal study, provide evidence of an association between the Asp299Gly polymorphism of the human TLR4 receptor and acute coronary syndromes. They confirm the previously reported involvement of TLR4 in carotid and femoral artery atherosclerosis.

The relevance of the TLR4 Asp299gly gene polymorphism in the susceptibility to duodenal ulcer and severity of gastric antral inflammation

The relevance of the TLR4 Asp299gly gene polymorphism in the susceptibility to duodenal ulcer and severity of gastric antral inflammation