Thr399Ile Single Nucleotide Polymorphisms Research Articles

Toll-like receptor-4 299Gly allele is associated with Guillain-Barré syndrome in Bangladesh.

ObjectiveTLR4 plays an important role in the pathogenesis of Guillain‐Barré syndrome (GBS). The relationships between TLR4 polymorphisms and susceptibility to GBS are poorly understood. We investigated the frequency and assessed the association of two single nucleotide polymorphisms (SNPs) in the extracellular domain of TLR4 (Asp299Gly and Thr399Ile) with disease susceptibility and the clinical features of GBS in a Bangladeshi cohort.MethodsA total of 290 subjects were included in this study: 141 patients with GBS and 149 unrelated healthy controls. The TLR4 polymorphisms Asp299Gly and Thr399Ile were genotyped using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay.ResultsThe minor 299Gly allele was significantly associated with GBS susceptibility (P = 0.0137, OR = 1.97, 95% CI = 1.17–3.31), and was present at a significantly higher frequency in patients with the acute motor axonal neuropathy (AMAN) subtype of GBS (P = 0.0120, OR = 2.37, 95% CI = 1.26–4.47) than acute inflammatory demyelinating polyneuropathy (AIDP) subtype (P = 0.961, OR = 1.15, 95% CI = 0.38–3.48); when compared to healthy controls. The genotype frequency of the Asp299Gly polymorphism was not significantly different between patients with GBS and healthy controls. The Asp299‐Thr399 haplotype was associated with a significantly lower risk of developing GBS (P = 0.0451, OR = 0.63, 95% CI = 0.40–0.99). No association was observed between the Thr399Ile polymorphism and GBS disease susceptibility.InterpretationThe TLR4 minor 299Gly allele was associated with increased susceptibility to GBS and the axonal GBS subtype in the Bangladeshi population. However, no associations were observed between the genotypes of the Asp299Gly and Thr399Ile SNPs and antecedent C. jejuni infection or disease severity in Bangladeshi patients with GBS.

Single nucleotide polymorphism of toll-like receptor 4 (TLR4) is associated with juvenile spondyloarthritis in Croatian population.

Single nucleotide polymorphisms (SNP) of toll-like and NOD-like receptors have been associated with altered receptor activity and modified production of proinflammatory cytokines leading to a number of diseases. Our aim was to determine whether SNP of TLR2 (Arg753Gln), TLR4 (Asp299Gly, Thr399Ile), and NLRP3 (Q705K) influence susceptibility to juvenile spondyloarthrtis (jSpA) and juvenile idiopathic arthritis (JIA). After the DNA extraction, 26 patients with jSpA, 11 with oligoarticular, polyarticular, or systemic JIA, and 40 healthy controls were genotyped for Arg753Gln, Asp299Gly, Thr399Ile, and Q705K SNP using real-time PCR-SNP analysis. Statistically significant difference in genotype frequency for Thr399Ile SNP of TLR4 was observed in the jSpA (χ2 = 6.705, p = 0.035) and not in the JIA group (χ2 = 3005, p = 0.223). Regarding Asp299Gly SNP, no significant difference in genotype frequency was found; however, allele frequency was significant in both jSpA and JIA patients. No significant difference in genotype or allele frequency was observed for Arg735Gln and Q705K SNP. The399Ile polymorphism of TLR4 may be responsible for altered immune response to microbial infection in variant carriers and represent a mechanism of triggering overproduction of proinflammatory cytokines and long-term inflammation in jSpA. SNP of TLR2, NLRP3, and TLR4 (Asp299Gly) were not associated with jSpA or JIA.

Polymorphisms of Toll-like receptors 2 and 4 in chronically infected hepatitis C patients from north-east Croatia.

Chronic infection with hepatitis C virus (HCV) is caused by an inadequate immune response. Experimental data suggest that the impaired activation of Toll-like receptors (TLRs) 2 and 4 contributes to chronic infection. We assessed the distribution of three single-nucleotide polymorphisms (SNPs) in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly/Thr399Ile) genes in individuals from north-east Croatia and their effect on the outcome of antiviral therapy. The study consisted of 60 chronically infected patients and 40 healthy subjects. TLR polymorphisms were determined by the PCR-based melting curve analysis. HCV genotyping was performed using the Linear Array Hepatitis C Virus Genotyping Test. Thirty-three patients were treated with standard interferon and ribavirin therapy, and their viral load was evaluated at weeks 28 and 53 after the beginning of therapy. The majority of chronic infections were caused by genotype 1 (77%), followed by genotypes 3 (15%) and 4 (7%). Patients with genotype 1 had higher viral loads than patients infected with other genotypes (P = 0.0428). Healthy individuals and patients with chronic infection had similar frequencies of TLR2-Arg753Gln and TLR4-Asp299Gly/Thr399Ile SNPs. Heterozygous and homozygous TLR4-Asp299Gly/Thr399Ile polymorphisms correlated with higher viral loads and delayed responses to antiviral therapy. We have provided the first evidence that TLR4 polymorphisms influence the success of antiviral therapy in our region. This suggests that therapeutic strategies should be adjusted not only according to HCV genotype but also to individual TLR polymorphism(s).

Association of Toll‐Like Receptor 4 Asp299Gly and Thr399Ile Polymorphisms with Increased Infection Risk in Patients with Advanced HIV‐1 Infection

BACKGROUND. The Toll-like receptor 4 (TLR4) is an essential component of the innate immune response to various microorganisms. We investigated the association between TLR4 polymorphism and the risk of acquiring severe infections, in patients with human immunodeficiency virus (HIV)-1 infection. METHODS. The presence of TLR4 Asp299Gly and Thr399Ile single nucleotide polymorphisms (SNPs) was determined in a cohort of 199 HIV-1 infected patients and evaluated in relation to the occurrence of various infections. RESULTS. One hundred seventy-two patients were homozygous for the wild-type genotype; 22 patients (11%) were heterozygous for both SNPs; 4 were heterozygous for 1 polymorphism; 1 patient was heterozygous for the Asp299Gly SNP and homozygous for the Thr399Ile SNP. Of individuals with a nadir CD4 cell count of <100 cells/mm(3), those who carried both SNPs, compared with those who carried the wild-type genotype, demonstrated a >3-fold increase in the odds ratio (OR) of any serious infection (OR, 6.33 vs OR, 1.83, P = .043). CONCLUSIONS. This study suggests an association between the presence of TLR4 Asp299Gly and Thr399Ile polymorphisms and the occurrence of serious infections in HIV-1 infected patients with a history of nadir CD4 cell count of <100 cells/mm(3).

The TLR4 ASP299GLY Polymorphism is a Risk Factor for Active Tuberculosis in Caucasian HIV-Infected Patients

Tuberculosis (TB) is a pandemic infectious disease especially frequent in HIV-infected patients. Toll-like receptor (TLR) 4 has been described to play a main role in the innate immunity against TB. In fact, single nucleotide polymorphisms (SNPs) in TLRs may influence AIDS disease progression. The association between two particular SNPs in human TLR4 (Asp299Gly and Thr399Ile) and active TB has been studied in non-HIV Africans with contradictory results. However, studies focusing on the effect of these TLR4 SNPs in active TB within a Caucasian HIV population are lacking. To analyze the association between TLR4 Asp299Gly and Thr399Ile SNPs and active TB, in Caucasian Mediterranean HIV-infected individuals. 468 HIV-infected patients were analyzed. TLR4 genotyping was performed by real-time PCR and melting curve technology. TB was diagnosed in 59 (12,6%) patients. In a bivariate analysis several variables resulted significantly associated with active TB; intravenous drugs use (OR= 2.2; 95% CI [1.2-3.8]), hepatitis C virus (HCV) co-infection (OR= 3.4; 95% CI [1.6-7.1]), CD4 count (p<0.001), HIV viral load (p=0.003), latent TB prophylaxis (OR= 0.3; 95% CI [0.1-0.5]), and TLR4 Asp299Gly (OR= 2.0; 95% CI [1.1-4.2]). No statistical association was found for the TLR4 Thr399Ile. After a multivariate analysis, HCV co-infection (OR= 3.8; 95% CI [2.2-6.5]), baseline CD4 count (OR= 0.996; 95% CI [0.994-0.998]), TLR4 Asp299Gly (OR= 2.57; 95% CI [1.18-5.61]) were independently associated with active TB and inversely with latent TB prophylaxis (OR= 0.24; 95% CI [0.01-0.60]). We describe an independent association between TLR4 Asp299Gly SNP and active TB in Caucasian Mediterranean HIV-infected patients.

Association of TLR4 Single-Nucleotide Polymorphisms and Sarcoidosis in Greek Patients

The present study investigates the potential role of Toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile single-nucleotide polymorphisms (SNPs) as risk factors in the development of sarcoidosis using a novel high-throughput microtiter well-based bioluminometric genotyping assay. One hundred and nineteen Greek patients with sarcoidosis and 209 control subjects were genotyped for the two SNPs of the TLR4 gene. The genotypes observed were in Hardy-Weinberg equilibrium. The heterozygote frequency for both SNPs in sarcoidosis group and control population was 13.4% (16/119) and 10.5% (22/209), respectively. The minor genotype was found to be the same for both sarcoidosis and control groups and similar to that found in other Caucasian populations. No significant association of Asp299Gly and Thr399Ile polymorphisms with increased susceptibility to sarcoidosis was found (p = 0.61 and odds ratio = 1.183). In conclusion, genotype data for the TLR4 Asp299Gly and Thr399Ile polymorphisms in the Greek population were found to be in linkage disequilibrium, and no contribution in the pathogenesis of sarcoidosis was established. Further, in course of the present study, we demonstrated a very simple and sensitive high-throughput bioluminometric assay for genotyping Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene.