Asp299Gly Single Nucleotide Polymorphisms Research Articles

Genotype Frequency of the Common TLR4 SNPs in a Kurdish Population: Global Reviews and Out-of-African Migrations.

Toll-like receptors (TLRs) are cellular innate immune receptors that explore microbial molecules. For instance, TLR4 can sense bacterial lipopolysaccharides, inducing cytokines and antimicrobial peptides against the bacteria. Single-nucleotide polymorphisms (SNPs) in TLR4 are associated with diseases such as septic shock. Therefore, investigations of common SNPs may help explain the pathogenesis of diseases and various innate immune responses to infections. This study investigated genotypic frequencies of the two common TLR4 SNPs, Asp299Gly and Thr399Ile, in a Kurdish population using restriction length fragment polymorphisms (RFLPs). Global frequencies of both TLR4 SNPs in different populations of sub-Saharan Africa, North Africa, western Asia, Eurasia, and East Asia were also used to infer human migrations and past settlements. The RFLP data demonstrate that, in the Kurdish population, the genotypic frequencies of both SNPs are similar to Iranian or other West Asian populations, which in turn are comparable to Eurasian populations, suggesting past admixture due to migrations, population intermixing, and common ancestry. Globally, the frequencies of the homozygous wild-types of TLR4 variants are prevalent, but homozygous mutants are rare or lacking in almost all global populations. Frequencies of the heterozygotes varied among populations. For instance, in sub-Saharan Africa the frequency of the Asp299Gly SNP is higher than that of Thr399Ile, whereas in the Arabian Peninsula both SNPs are present at high frequencies. In contrast, East Asian populations lack or have very low frequencies of both TLR4 SNPs of interest. Moreover, co-segregation of the TLR4 SNPs is common in some populations, which may indicate important associations with certain diseases. Future studies are required to link the TLR4 SNPs with either resistance or susceptibility to diseases.

Role of toll-like receptor 4 Asp299Gly polymorphism in the development of cardiovascular diseases in HIV-infected patients

Cardiovascular diseases (CVDs) are one of the main causes of morbimortality in HIV-infected patients on suppressive antiretroviral therapy. The objective of this work was to evaluate the role of single nucleotide polymorphisms (SNPs) in lipopolysaccharide (LPS) Toll-like receptor 4 (TLR4) and CVDs occurrence in HIV-infected patients. Additionally, the functional consequences of carrying these SNPs were analyzed. The association of TLR4 SNPs, Asp299Gly/Thr399Ile with CVDs occurrence was analyzed using multivariate logistic regression models. Clinical, immunological, and traditional cardiovascular risk factors were used as covariates. The monocyte phenotype and response were assessed by multiparametric flow cytometry comparing carriers with noncarriers of this SNP. Asp299Gly SNP, assayed in 253 HIV-infected patients, was independently associated with the occurrence of CVDs after adjusting for CD4+ T-cell nadir, HCV-coinfection, bacterial pneumonia, diabetes mellitus, and traditional cardiovascular risk factors [odds ratio (confidence interval 95%) = 3.672 (1.061-12.712), P = 0.04). Carriers of Asp299Gly SNP showed higher percentage of patrolling and intermediate monocytes producing a proinflammatory combination of cytokines compared with noncarriers (P = 0.037 and P = 0.046, respectively). Intermediate monocyte subset levels correlated with soluble interleukin-6 levels only in carriers (r = 0.89; P = 0.01). TLR4 Asp299Gly polymorphism is independently associated with the occurrence of CVDs in HIV-infected patients. The proinflammatory profile associated to this variant could be involved in the development of atherosclerotic pathologies.

TLR4 Asp299Gly polymorphism may be protective against chronic periodontitis.

Periodontitis results from interplay between genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in the coding region of the toll-like receptor 4 gene (TLR4) may be associated with periodontitis, although previous studies have been inconclusive. Moreover, the interaction between environmental factors, such as cigarette smoking (a major risk factor for periodontitis), and Porphyromonas gingivalis (a major periodontal pathogen) with the TLR4 coding region Asp299Gly SNP (rs4986790; a SNP associated with lipopolysaccharide-mediated inflammatory responses in periodontitis), have been largely ignored in previous reports. Therefore, the objective of this study was to examine the association between TLR4 Asp299Gly (rs4986790) with alveolar bone height loss (ABHL) and periodontitis, accounting for interactions between this SNP with smoking and P.gingivalis prevalence. The CD14/-260 SNP (rs2569190) served as a control, as a recent meta-analysis suggested no relationship between this SNP and periodontitis. This multicenter study included 617 participants who had rheumatoid arthritis or osteoarthritis. This report presents a secondary outcome from the primary case-control study examining the relationship of periodontitis with established rheumatoid arthritis. The Centers for Disease Control/American Academy of Periodontology case definitions of periodontitis were used for this analysis. Participants received a full-mouth clinical periodontal examination and panoramic radiograph. Percentage ABHL was measured on posterior teeth. The TLR4 Asp299Gly and CD14/-260 SNPs were selected a priori and genotypes were determined using the ImmunoChip array (Illumina(®) ). Minor allele frequencies and associations with periodontitis and ABHL did not differ according to rheumatoid arthritis vs. osteoarthritis status; therefore, data from these two groups were pooled. The presence of P.gingivalis was detected in subgingival plaque by PCR. Multivariate ordinal logistic regression examined associations between the SNPs and periodontitis or ABHL. SNP interactions with smoking and P.gingivalis were analyzed. A significant, negative interaction was observed between the TLR4 SNP and the presence of P.gingivalis (p=0.045) with respect to periodontitis. The TLR4 minor variant was also associated with less ABHL: 16.8% of individuals with low ABHL, 9.0% with moderate ABHL and 11.2% with high ABHL had the minor allele [p=0.029; odds ratio=0.58 (95% confidence interval: 0.36-0.95)]. The interaction between the TLR4 SNP and smoking was not significant with respect to periodontitis or ABHL. The CD14 SNP was not associated with periodontitis or ABHL. The TLR4 Asp299Gly SNP significantly interacted with P.gingivalis in conferring a decreased risk of periodontitis and may be protective against ABHL, a feature of periodontitis. Agents blocking TLR4 signaling, a strategy currently under investigation for the treatment of other inflammatory conditions, may warrant investigation in the context of periodontitis related to the presence of P.gingivalis.

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.

Track B Clinical Science

BackgroundToll-like receptors (TLRs) are transmembrane receptors that activate cells of the innate immune systems upon recognition of pathogen-associated molecular patterns. The TLR4 is an essential component of the innate immune response to various microorganisms. We investigated the impact of TLR4 polymorphism on development of opportunistic diseases in HIV-infected patients.MethodsThe presence of TLR4 Asp299Gly single nucleotide polymorphisms (SNPs) was determined in a cohort of 180 antiretroviral treatment-naive HIV-1 infected patients and evaluated in relation to the occurrence of opportunistic infections. TLR4 genotyping was performed by real-time PCR.ResultsOne hundred sixty-five patients were homozygous for the wild-type genotype (AA); 15 patients (8,3%) were heterozygous for the Asp299Gly SNP (AG).TLR4 polymorphism was associated with more frequent development of the opportunistic infections, such as active tuberculosis (OR=3.27; 95% CI [1.21–10.29]), herpes zoster (OR=4.15; 95% CI [1.24–7.29]) and toxoplasmosis (OR=6.23; 95% CI [1.19–18.67]) compared with genotype AA.In addition, TLR4 SNP was associated with development of opportunistic diseases among individuals with CD4 cell count of>100 cells/mm3, compared with homozygous HIV-infected patients (OR, 5.25; 95%, CI [2.28–10.47]).ConclusionThis study suggests a greater risk of developing of active tuberculosis and other opportunistic infections in patients with the Asp299Gly TLR4 polymorphism.

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.

CD14 C-159T and Toll-Like Receptor 4 Asp299Gly Polymorphisms in Surviving Meningococcal Disease Patients

BackgroundCarriage of Neisseria meningitidis occurs approximately in 10% of the population, onset of invasive meningococcal disease (IMD) cannot be predicted and differs between ages. It remains unclear, which host factors determine invasion of the bloodstream by the bacteria. Innate immunity has a very important role in the first recognition of invading pathogens. The functional single nucleotide polymorphisms (SNPs) CD14 C-159T and toll-like receptor 4 (TLR4) Asp299Gly have been associated with the risk of gram-negative infections. However, their role in development of IMD still remains unclear. Our aim was to investigate the influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of IMD.Methodology/Principal FindingsIt was a retrospective case control study. Surviving Austrian meningococcal disease patients were enrolled by sending buccal swabs for DNA analysis. 185 cases with a proven meningococcal infection and 770 healthy controls were enrolled. In surviving meningococcal disease patients DNA analysis of CD14 C-159T and TLR 4 Asp299Gly polymorphisms was performed, as they are part of the innate immune response to bacterial determinants. CD14 C-159T and TLR4 Asp299Gly SNPs were not significantly associated with the presence of IMD when compared to healthy controls. The odds ratio for CD14 C-159T SNP was 1.14 (95% confidence interval (CI) 0.91–1.43; p = 0.266). In TLR4 Asp 299 Gly SNP the odds ratio was 0.78 (CI 0.47–1.43; p = 0.359).Conclusion/SignificanceWe could not observe a significant influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of developing IMD in surviving meningococcal disease patients. To our knowledge, this is the first study investigating the influence of the CD14 C-159T SNP on the susceptibility to IMD.