Toll-like Receptor 4 Polymorphisms Research Articles

Association of maternal Toll-like receptor-4 alleles with susceptibility to early-onset preeclampsia in central Greece.

Altered maternal inflammatory responses may play a role in the development of hypertensive disorders of pregnancy like preeclampsia, its more severe early-onset form and intrauterine growth restriction. We evaluated the relation of common allelic variants of Toll-like receptor 4 (TLR4), known to impair the inflammatory response, with the susceptibility to early-onset preeclampsia in Central Greece. We compared the occurrence of TLR4 (Asp299Gly and Thr399Ile) alleles in heterozygous (A/G, C/T) and homozygous (G/G, T/T) states in 84 women with a history of early-onset preeclampsia and 94 age matched controls with a history of only uneventful pregnancies, by direct sequencing. Heterozygous TLR4 allelic variants were more common in women with a history of early-onset preeclampsia than in controls (GA for Asp299Gly: 14.3% vs 6.4% (AA), p = 0.053 & CT for Thr399Ile: 16.7% vs. 6.4% (CC), p = 0.019) and a stronger association was obtained when homozygous allelic carriers were also included (GA/GG for Asp299Gly: 16.7% vs. 6.4% (AA), p = 0.03 & TC/TT for Thr399Ile: 19.0% vs. 6.4% (CC), p = 0.01). We recorded association between common TLR4 gene variants and early-onset preeclampsia. Our findings support the involvement of maternal innate immune system in severe hypertensive disorders of pregnancy and point to the potential value of maternal TLR4 polymorphisms as predictors-risk factors of susceptibility to early-onset preeclampsia in Central Greece.

Single nucleotide polymorphisms of Toll-like receptor-4 and of autophagy-related gene 16 like-1 gene for predisposition of premature delivery: A prospective study.

To investigate the impact of carriage of single nucleotide polymorphisms (SNPs) of the Toll-like receptor-4 (TLR4) and of autophagy-related gene 16-like-1 (ATG16L1) in preterm delivery (PTD).A prospective cohort of 145 pregnant women was studied. Women were prospectively followed-up until delivery. Genotyping for rs4986790 (Asp299Gly transition) and rs4986791 (Thr399Ile transition) of TLR4 and for rs2241880 of ATG16L1 was done by PCR-restriction fragment length polymorphism. The primary study endpoint was the impact of carriage of minor alleles of TLR4 on early PTD before gestational week 32. Associations with human chorionic gonadotrophin (hCG) were also analyzed. Peripheral blood mononuclear cells were isolated from 15 healthy women and stimulated for cytokine production.No difference in clinical characteristics was observed between women delivering full term and preterm. The frequency of early PTD was 25% among women carrying minor alleles of TLR4 and 6.8% among women carrying major alleles (P: .032). Odds ratios for PTD were 3.85 among women carrying the GG genotype of rs2241880 and major alleles of TLR4 and 0.26 among carriers of GG genotype and minor alleles of TLR4 (P: .030). The co-presence of GG genotype of rs2241880 and hCG above 70 U/L was an independent variable for PTD. Stimulated production of interleukin-6 was greater among women with GG genotypes of rs2241880.Minor alleles of SNPs of TLR4 predispose to early PTD. The GG genotype of rs2241880 of ATG16L1 is associated with PTD when hCG is supra-elevated.

Toll Like Receptor 2 Genotypes and Intra-Coronary Stent Restenosis

AbstractBackground: Intra-coronary Stent Restenosis (ISR) is a common complication after Percutaneous Coronary Interven-tion (PCI). There is an association between many genes such as Toll Like Receptor 2 (TLR2), Adrenergic B2 Receptor (ADRB2), platelet glycoprotein IIIa, Nitric Oxide Synthase3 (NOS3), P2Y12 receptor (P2Y12), cyclin-dependent kinase inhibitor (p27kip1) and the process of intra-coronary stent restenosis. Study of the genetic polymorphisms of these genes is very important to detect which is protective against intra-coronary stent restenosis, and which is risky for development of this problem. Our study selected TLR2 gene to detect its different genotypes involved in the problem of ISR.Aim of Study: To find the association between TLR2 genotypes, polymorphisms and Intra-coronary Stent Restenosis (ISR) complication after PCI procedures.Patients and Methods: The study included 200 patients with previous coronary revascularization by stent implantation. All patients were re-admitted to coronary angiography because of objective evidence of myocardial ischemia. The patients were classified into two groups: Group (A) included 100 patients who developed ISR and Group (B) included 100 patients who did not develop ISR. The two groups were compared regarding distribution of TLR2 genotypes and alleles.Results: 78% of patients with (GG) genotype, 14% of patients with (GA) genotype and 7% of patients with (AA) genotype developed ISR. There was no association between TLR2 (GA), (AA) genotypes and risk of ISR when compared by (GG) wild homozygous genotype (p>0.05, OR=1.2). We also did not find any association between TLR2 gene alleles and risk of ISR complication (p>0.05, OR=0.9).Conclusion: There was no association between different TLR2 genotypes, alleles and risk of ISR development.

Genetic polymorphisms in pattern recognition receptors are associated with allergic diseases through gene-gene interactions.

There is evidence that suggests variation in gene encoding pattern recognition receptors, the essential components of innate immunity, might be associated with atopic diseases. However, results have been inconclusive. The aim of the study was to determine the individual associations and possible interactive effects of the CD14 (cluster of differentiation 14), TLR4 (toll-like receptor 4) and TLR2 (toll-like receptor 2) polymorphisms on allergic diseases. The CD14 C-159T, TLR4 +896A/G and TLR2 A-16934T polymorphisms were identified in 115 children aged from 6 to 17 years. All subjects were selected using a detailed questionnaire which included questions on symptoms and each one underwent skin prick testing. All single-nucleotide polymorphisms (SNPs) were determined using real-time polymerase chain reaction (PCR) assays. There was no statistically significant correlation between the 3 polymorphisms (CD14 C-159T, TLR4 +896A/G and TLR2/-16934A/T) and either asthma, allergic rhinitis or atopy. We observed that children who were heterozygous or homozygous for both the CD14/-159T and TLR2/-16934A alleles had a 4-fold lower risk for asthma than children who were carriers of the T allele of CD14 but non-carriers of the A allele of TLR2, and an almost 3-fold lower risk for asthma when compared to all other groups. Concerning allergic rhinitis, a similar trend was observed. In addition, the presence of at least 1 A allele in the TLR2/-16934 polymorphism reduced the risk for asthma and allergic rhinitis, but only in children who were homozygous for the common A allele in the TLR4 +896 polymorphism. Our study supports the idea that the CD14, TLR2 and TLR4 polymorphisms may not be directly involved in the development of atopic diseases. However, our results suggest that their impact on the risk of asthma and allergic rhinitis might be modulated by gene-gene interactions.

Genetic polymorphisms in toll-like receptors 1, 2, and 4 in feline upper respiratory tract aspergillosis

Fungal species in the genus Aspergillus are environmental saprophytes that can act as opportunistic pathogens of the nasal cavity and paranasal sinuses in humans, cats and other species. Upper respiratory tract aspergillosis (URTA) presents as non-invasive and invasive forms with the latter occurring almost exclusively in immunocompromised hosts. However, in domestic cats, invasive URTA affects apparently immunocompetent patients. A defect in innate immunity has been proposed as a predisposing factor in invasive feline URTA. Single nucleotide polymorphisms (SNPs) in pattern recognition receptor genes have been implicated in the pathogenesis of aspergillosis in humans. The aims of this study were to identify non-synonymous SNPs in the coding regions of toll-like receptors involved in the immune response to Aspergillus spp. and to compare the frequency of these SNPs between affected and control cats. The coding and flanking regions of TLR1, TLR2 and TLR4 were sequenced in 14 cats with URTA and the sequences were compared with those in 20 control cats without aspergillosis. In total, 23 non-synonymous SNPs were identified in TLR1 (n = 11), TLR2 (n = 3) and TLR4 (n = 10). Differences in allelic frequency of non-synonymous SNPs between affected and controls were not identified either within breeds or overall or between non-invasive and invasive disease phenotypes. Although allelic frequency differed between cat breeds that are overrepresented for URTA and underrepresented breeds there was no association differences identified between affected cats and underrepresented breeds. The difference in allelic frequency of an INDEL point mutation identified in intron 1 of TLR4, between cats with non-invasive versus invasive aspergillosis approached significance (p = 0.054). While results from this study do not support a role for non-synonymous SNPs in the pathogenesis of feline URTA they do provide evidence that investigation for polymorphisms in non-coding regions of these genes and in other pattern recognition receptors are warranted.

Associations between TLR4 Polymorphisms and Open Angle Glaucoma: A Meta-Analysis.

Background Previous studies exploring the association between toll-like receptor 4 (TLR4) polymorphisms and open angle glaucoma (OAG) presented inconsistent results. We aimed to investigate the association between TLR4 polymorphisms and OAG. Methods A systematic literature search was conducted in PubMed, EMBASE, ISI Web of Knowledge, and the Cochrane Library up to 31 December 2018. Odds ratio (OR) and 95% confidence interval (95%CI) were calculated, followed by stratification analyses according to ethnicity and glaucoma subtype. Results TLR4 rs7037117 polymorphism had significant associations with increased risk of OAG in allelic model (OR=1.25; 95%CI: 1.09-1.44; P=0.002) and recessive model (OR=1.49; 95%CI: 1.08-2.04; P=0.01). With regard to rs10759930, rs12377632, and rs2149356, the results showed significant increased risks in all genetic models (all P<0.05), whereas, for rs1927914, rs11536889, and rs7045953, no significant associations were identified in any genetic model (all P>0.05). Furthermore, the association of rs1927911 with OAG risk was found to be significant in recessive model (OR=1.34; 95%CI: 1.06-1.71; P=0.02). As for rs4986790 and rs4986791, meta-analyses were not performed due to the limited number of studies and the ethnic differences. Subgroup analysis indicated that the above polymorphisms with significant differences might increase the susceptibility in POAG patients. As for the ethnicity, rs7037117, rs10759930, and rs1927911 might increase the risk in Asians, while rs12377632 and rs2149356 might increase the risk in Asians and Mexicans. Conclusion The meta-analysis highlighted that certain mutations of some TLR4 polymorphisms might increase the susceptibility of OAG. However, TLR4 polymorphisms are still far from being candidate genetic biomarkers for OAG. Additional researches involving larger scale epidemiological studies are warranted to validate our results.

Association of Nod‐like receptor protein‐1 (rs2670660) and Toll‐like receptor‐4 (rs4986790) with non‐segmental vitiligo: A case–control study in South Indian population

Non-segmental vitiligo (NSV) is an autoimmune skin disease. Genetics plays a predominant part in disease pathogenesis. Nucleotide-binding and oligomerization domain (NOD)-like receptors and pyrin-containing protein (NLRP) and Toll-like receptors (TLR) are pattern recognition receptors in mediating innate immunity. They participate in presenting pathogens and mediating the immune responses. NLRP and TLRs are involved in mediating immune response in various dermatological diseases. Understanding the influence of genetic polymorphisms of NLRP and TLRs associated with immune homeostasis might help us to understand the complex etiopathogenesis of NSV. Thus, we aimed to study the association of NLRP-1 (rs2670660) and TLR-4 (rs4986790) and the synergistic effects on disease spectrum, disease activity of NSV in South Indian population. This research was designed as a case-control genetic study with 264 patients and 264 controls. Genotyping of NLRP-1 (rs2670660) and TLR-4 (rs4986790) was performed by Taqman 5' allele discrimination assay and ARMS-PCR. Plasma levels of proteins were measured by enzyme-linked immunosorbent assay (ELISA). A statistically significant difference was observed with the frequency of homozygous GG genotype of NLRP-1 (rs2670660) (17.8% in cases vs. 5.3% in controls) (p<0.0001; OR-3.73; 95% CI-1.94-7.14). Allele G was significantly frequent in 38% of the cases than in controls with 30% (p=0.004; OR-1.46; 95% CI-1.13-1.89). Plasma NLRP-1 level was significantly higher in patients compared to controls (p<0.05). Amongst cases, the plasma NLRP-1 levels did not show any difference with respect to their genotypes (p>0.05). In TLR-4 (rs4986790), no significant difference in the frequency of genotypes and allele between cases and controls (p=0.80) was observed; nevertheless, plasma TLR-4 was analogous between cases and controls (p>0.05). Influence of genotype on plasma TLR-4 showed no significant difference in TLR-4 levels between GG and ancestral genotype AA, whilst heterozygous AG genotype showed a significant increase of TLR-4 compared to AA and GG (p=0.02) amongst NSV cases. The obtained results suggest that NLRP-1 (rs2670660), and not TLR-4 ((rs4986790), is associated with increased risk of NSV in South Indian population.

Single-nucleotide polymorphisms in Toll-like receptor genes are associated with the prognosis of gastric cancer and are not associated with Helicobacter pylori infection

Toll-like receptors (TLRs) mediate the recognition of Helicobacter pylori (H. pylori) and initiate the innate immune response to infection. Genetic polymorphisms of TLRs play important roles in gastric carcinogenesis. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) in TLR genes and H. pylori infection in the prognosis of gastric cancer (GC). A total of 756 GC patients were included in this study. Nine SNPs (TLR2: rs3804100, rs7696323, and rs10116253; TLR4: rs10983755, rs11536878, rs1927914, and rs7873784; TLR5: rs5744174; and TLR9: rs187084) in TLR genes were genotyped by MassARRAY assay. Kaplan-Meier survival curves and Cox regression were employed to conduct the associations between SNPs in TLRs and the survival of GC. Multivariate Cox regression indicated that patients with the TLR2 rs3804100 TT genotype exhibited worse survival than those with the CC + CT genotype (HR = 1.262, 95% CI: 1.006–1.582). No significant interaction between rs3804100 and H. pylori infection was observed for the prognosis of GC. Our results suggested that the TLR2 rs3804100 polymorphism may be a potential prognostic biomarker for GC independent of the H. pylori infection-related pathway.

Toll-like receptor polymorphism in host immune response to infectious diseases: A review.

Immunopolymorphism is considered as an important aspect behind the resistance or susceptibility of the host to an infectious disease. Over the years, researchers have explored many genetic factors for their role in immune surveillance against infectious diseases. Polymorphic characters in the gene encoding Toll-like receptors (TLRs) play profound roles in inducing differential immune responses by the host against parasitic infections. Protein(s) encoded by TLR gene(s) are immensely important due to their ability of recognizing different types of pathogen associated molecular patterns (PAMPs). This study reviews the polymorphic residues present in the nucleotide or in the amino acid sequence of TLRs and their influence on alteration of inflammatory signalling pathways promoting either susceptibility or resistance to major infectious diseases, including tuberculosis, leishmaniasis, malaria and filariasis. Population-based studies exploring TLR polymorphisms in humans are primarily emphasized to discuss the association of the polymorphic residues with the occurrence and epidemiology of the mentioned infectious diseases. Principal polymorphic residues in TLRs influencing immunity to infection are mostly single nucleotide polymorphisms (SNPs). I602S (TLR1), R677W (TLR2), P554S (TLR3), D299G (TLR4), F616L (TLR5), S249P (TLR6), Q11L (TLR7), M1V (TLR8), G1174A (TLR9) and G1031T (TLR10) are presented as the major influential SNPs in shaping immunity to pathogenic infections. The contribution of these SNPs in the structure-function relationship of TLRs is yet not clear. Therefore, molecular studies on such polymorphisms can improve our understanding on the genetic basis of the immune response and pave the way for therapeutic intervention in a more feasible way.

Polymorphism in Toll-Like Receptors and Helicobacter Pylori Motility in Autoimmune Atrophic Gastritis and Gastric Cancer.

Autoimmune atrophic gastritis (AAG) is associated with an increased risk of certain types of gastric cancer (GC). Helicobacter pylori (H. pylori) infection may have a role in the induction and/or maintenance of AAG and GC. Toll-like receptors (TLR) are essential for H. pylori recognition and subsequent innate and adaptive immunity responses. This study therefore aimed to characterize TLR polymorphisms, and features of bacterial flagellin A in samples from patients with AAG (n = 67), GC (n = 114) and healthy donors (HD; n = 97). TLR5 rs5744174 C/C genotype was associated with GC, lower IgG anti H. pylori response and a higher H. pylori flagellin A abundance and motility. In a subset of patients with AAG, H. pylori strains showed a reduction of the flagellin A abundance and a moderate motility compared with strains from GC patients, a prerequisite for active colonization of the deeper layers of the mucosa, host immune response and inflammation. TLR9 rs5743836 T allele showed an association with serum gastrin G17. In conclusion, our study suggests that alterations of flaA protein, moderate motility in H. pylori and two polymorphisms in TLR5 and TLR9 may favor the onset of AAG and GC, at least in a subset of patients. These findings corroborate the function of pathogen–host cell interactions and responses, likely influencing the pathogenetic process.

Susceptibility to infection with Borrelia afzelii and TLR2 polymorphism in a wild reservoir host

The study of polymorphic immune genes in host populations is critical for understanding genetic variation in susceptibility to pathogens. Controlled infection experiments are necessary to separate variation in the probability of exposure from genetic variation in susceptibility to infection, but such experiments are rare for wild vertebrate reservoir hosts and their zoonotic pathogens. The bank vole (Myodes glareolus) is an important reservoir host of Borrelia afzelii, a tick-borne spirochete that causes Lyme disease. Bank vole populations are polymorphic for Toll-like receptor 2 (TLR2), an innate immune receptor that recognizes bacterial lipoproteins. To test whether the TLR2 polymorphism influences variation in the susceptibility to infection with B. afzelii, we challenged pathogen-free, lab-born individuals of known TLR2 genotype with B. afzelii-infected ticks. We measured the spirochete load in tissues of the bank voles. The susceptibility to infection with B. afzelii following an infected tick bite was very high (95%) and did not differ between TLR2 genotypes. The TLR2 polymorphism also had no effect on the spirochete abundance in the tissues of the bank voles. Under the laboratory conditions of our study, we did not find that the TLR2 polymorphism in bank voles influenced variation in the susceptibility to B. afzelii infection.

The association of toll-like receptor 4 gene polymorphisms with primary open angle glaucoma susceptibility: a meta-analysis.

Primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) cause irreversible blindness while current medications cannot completely inhibit disease progression. An understanding of immunopathogenesis is thus a keystone to develop novel drug targets and genetic markers are still required for early diagnosis. Toll-like receptor 4 (TLR4) is an essential player in inflammation in various diseases. However, the TLR4 polymorphisms have not been completely elucidated in both types of glaucoma. The aim of the present study was to identify the association between TLR4 polymorphism and glaucoma (POAG and NTG) via the use of a comprehensive review and meta-analysis. The relevant studies were collected from PubMed, Excerpta Medica Database (EMBASE), and Web of Science to identify eight included articles, assessed for quality by a modified Newcastle-Ottawa Scale (NOS) for gene association study. A meta-analysis was applied to calculate the pooled odds-ratio and 95% confidence intervals (CIs) to evaluate the association between TLR4 polymorphism and glaucoma. The results revealed that TLR4 rs1927911 A/G, rs12377632 C/T, and rs2149356 G/T significantly decrease the risk of POAG and NTG in allele contrast models 0.71-, 0.71-, and 0.67-fold, respectively. Moreover, rs4986790 A/G and rs4986791 C/T showed a stringent association with POAG in allele contrast, heterozygous, recessive, and overdominant models. In conclusion, this meta-analysis represented a significant correlation between TLR4 polymorphisms and both types of glaucoma suggesting that TLR4 might be involved in the pathogenesis of glaucoma and may be applied as a genetic marker for disease screening.

The interaction effects between TLR4 and MMP9 gene polymorphisms contribute to aortic aneurysm risk in a Chinese Han population

BackgroundA cross-talk between Toll-like receptor 4 (TLR4) and matrix metalloproteinase 9 (MMP9) plays a vital role in aortic pathophysiology. The objective of this study was to evaluate the interactions between TLR4 and MMP9 polymorphisms in the risk of aortic aneurysm (AA) and its subtypes.MethodsKASP method was used to detect polymorphisms of TLR4 (rs11536889 and rs1927914) and MMP9 (rs17576) in 472 AA patients and 498 controls. According to location and size, AA patients were further classified into abdominal AA (AAA), thoracic AA (TAA), and large AA (>5.0 cm), small AA(≤5.0 cm), respectively.ResultsThe significant interaction effect of TLR4rs1927914 with MMP9rs17576 polymorphisms was observed for the risk of TAA (Pinteraction = 0.038, OR = 6.186) and large AA (Pinteraction = 0.044, OR = 5.892). There were epistatic effects between TLR4rs1927914 and MMP9rs17576 polymorphisms on the risk of overall AA, AAA, TAA and large AA when they were present together. Moreover, the cumulative effects of the pairwise interaction TLR4rs1927914-MMP9rs17576 were associated with an increased risk of overall AA (Ptrend = 0.032) and AAA (Ptrend = 0.031).ConclusionsThe novel interaction between TLR4rs1927914 and MMP9rs17576 polymorphisms could increase the risk of AA disease or its subtypes by exerting epistatic and cumulative effects.

Polymorphisms in Toll-Like Receptors (TLRs)-7 and 9 Genes in Indian Population with Progressive and Nonprogressive HIV-1 Infection.

The polymorphisms in Toll-like receptor (TLR) 7 and 9 genes are shown to influence HIV-1 infection. We studied HIV-1-infected Indian individuals for presence and association of TLR7 and 9 gene polymorphism with different disease outcomes. Genomic DNA from 65 HIV-infected individuals (35 long-term nonprogressors and 30 progressors) and 89 uninfected healthy donors was isolated, amplified, and sequenced for the reported polymorphisms in TLR7 [Gln11Leu (A/T); rs179008] and TLR9 (1635A/G; rs352140) genes. Of these, only the reported TLR9 single-nucleotide polymorphism [SNP; p = .017, odds ratio (OR) = 0.20] and its allele A frequency (p = .038, OR = 0.41) were found to be associated with slow disease progression. Of the new SNPs observed (three TLR7 and two TLR9), the TLR7 rs2074109 G allele showed less likely association with HIV-1 acquisition (p = .019, OR = 0.27). These findings indicate that TLR7 SNP (rs2074109) could be one of the factors for predisposition to HIV-1 and TLR9 1635A/G genotype and allele might have a role in HIV-1 disease progression in Indian population.

Агрегационная активность тромбоцитов у больных ишемическим инсультом - носителей генетического полиморфизма некоторых толл - подобных рецепторов

Цель - изучение генетического полиморфизма толл-подобных рецепторов при ишемическом инсульте и его влияние на агрегационную активность тромбоцитов. Методика. В исследовании приняли участие 115 больных ишемическим инсультом, в возрасте 55-65 лет и 94 сопоставимых по возрасту здоровых респондента. Материалом для молекулярно-генетического анализа служили образцы ДНК, выделенные из лейкоцитов периферической крови. Первичный гемостаз (спонтанная и индуцированная агрегатометрия) изучался на двухканальном лазерном анализаторе агрегации тромбоцитов АЛАТ-2. Результаты показали, что предикторами ишемического инсульта являются аллели: 753Arg TLR2, 249Pro TLR6, 1237C TLR9 и генотипы 753Arg/Arg TLR2, 299Asp/Asp TLR4, 249Pro/Pro TLR6 с отношением шансов от 1,49 до 3,35. Для развития инсульта имеет значение не только качество полиморфных маркеров, но и количество предикторных аллельных вариантов. У больных ишемическим инсультом в острейший период и в период формирования инфаркта мозга отмечается увеличение скорости и степени спонтанной агрегации тромбоцитов с последующим снижением к концу острого периода. При внесении АДФ (5 и 1,25 мкг/мл) и коллагена наблюдается снижение скорости и степени агрегации на 1-е и 10-е сут инсульта с увеличением таковых к 21-м сут. У больных - обладателей двух и более предиктивных аллелей полиморфизма толл-подобных рецепторов в геноме в динамике инсульта отмечаются сравнительно низкие показатели степени и скорости индуцированной агрегации тромбоцитов с увеличением радиуса агрегатов. Aim. To study genetic polymorphism of toll-like receptors in ischemic stroke and the polymorphism effect on the platelet aggregation ability. Methods. The study involved 115 patients with ischemic stroke aged 55-65 and 94 age-matched healthy respondents. DNA samples isolated from peripheral blood leukocytes were used for molecular genetic analysis of TLR2 (Arg753Gln), TLR3 (Phe412Leu), TLR4 (Asp299Gly), TLR6 (Ser249Pro), TLR9 (T - 1237 C). Primary hemostasis (spontaneous and induced aggregatometry) was studied using an ALAT-2 two-channel laser analyzer of platelet aggregation. Results. The study showed that predictors of ischemic stroke included the 753Arg TLR2, 249Pro TLR6, 1237C, and TLR9 alleles and the -753Arg/Arg TLR2, 299Asp/Asp TLR4, and 249Pro/Pro TLR6 genotypes with odds ratios from 1.49 to 3.35. Not only the quality of polymorphic markers but also the number of predictive allelic variants are important for the development of stroke. In patients with ischemic stroke in the acute phase and during the formation of cerebral infarction, increased rate and degree of spontaneous platelet aggregation were observed with a subsequent decrease by the end of acute period. Addition of ADP (5 and 1.25 mg/ml) and collagen decreased the rate and degree of platelet aggregation on days 1 and 10 of stroke with an increase in both by day 21. In patients carrying two or more predictive alleles of the toll-like receptor polymorphism in the genome, relatively low rate and degree values of induced platelet aggregation with increased radius of the aggregates were observed in the dynamics of stroke

Association between a single nucleotide polymorphism of toll-like receptor 4 and the response to direct-acting antiviral therapy in patients with chronic hepatitis C

Association between a single nucleotide polymorphism of toll-like receptor 4 and the response to direct-acting antiviral therapy in patients with chronic hepatitis C

Breed-specific variations in the coding region of toll-like receptor 4 in the domestic cat

Specific point mutations in the human toll-like receptor 4 (TLR4) confer altered risk for diverse diseases including sepsis, aspergillosis and inflammatory bowel disease. Some of these TLR4 polymorphisms are racially specific. We hypothesised that feline TLR4 polymorphisms might underlie an observed increased risk to infectious and inflammatory diseases in some cat breeds. The aim of this study was to identify breed-specific variations in the coding region of feline TLR4 and to model the effect of mutations on protein structure and function in silico. The entire coding region of TLR4 was sequenced in 8 groups (7 pure-bred, 1 crossbred) of domestic cats (Felis catus) comprising 158 individuals. Twenty-two single nucleotide polymorphisms (SNPs) were identified in TLR4, with 16 located in the coding region (11 non-synonymous) and four in the 3′UTR. Comparison of breed specific allelic frequencies indicated that Burmese and British shorthairs most commonly differed from other breeds. In silico analyses to predict the impact of the 11 non-synonymous variants indicated a deleterious effect on protein structure for one SNP (c.869 G > A), which was not associated with a specific breed. Overall, findings from this study do not support a role of TLR4 dysfunction in breed-predispositions to infectious diseases in domestic cats in Australia.

The associations between Toll-like receptor 4 gene polymorphisms and hepatitis C virus infection: a systematic review and meta-analysis.

Background and objective: The hepatitis C virus (HCV) is able to cause a life-threatening disease relating to lethal hepatocellular carcinoma. Previous, Toll-like receptor polymorphisms were proposed as promising biomarker for HCV-related hepatocellular carcinoma and disease progression. This study aimed to summarize the association of TLR4 polymorphisms and HCV infection through meta-analysis.Methods: We applied a systematic review and meta-analysis performed by using PubMed, EMBASE and Web of Science searches. The Modified Newcastle-Ottawa scale was used for quality assessment. The odd-ratio (OR) and 95% confidence interval (CI) were calculated to assess the association. In silico analysis was applied for proposing the function as microRNA (miRNA) of non-coding polymorphism. Finally, the miRNA target was predicted and annotated to suggest the possible relationship between polymorphism and HCV infection.Results: Our meta-analysis incorporated seven studies involving rs4986791, rs4986790 and rs2149356. No association exists between rs4986791 and HCV infection. However, the heterozygous model (AG vs GG) of rs4986790 significantly associates with HCV infection (OR = 0.33, 95% CI = 0.21–0.49, P<0.0001). Moreover, the rs2149356 TG genotype also associates with HCV infection in the over-dominant model (TG vs TT+TG: OR = 0.54, 95% CI = 0.40–0.75). In silico analysis of rs2149356G allele showed that this mutation is siRNA, which targets the set of genes, especially in the autophagy pathway.Conclusion: We demonstrated that rs4986790 and rs2149356 are associated with HCV infection.

A single-nucleotide polymorphism in TLR4 is linked with the risk of HIV-1 infection

ABSTRACTIntroduction: Toll-like receptors (TLRs) are pattern recognition receptors that play a role in innate immunity. Mounting evidence shows that single-nucleotide polymorphisms (SNPs) in TLRs link to various infectious diseases, including human immunodeficiency virus (HIV). We hypothesized links between two TLR4 SNPs (rs4986790 leading to Asp299Gly and rs4986791 leading to Thr399Ile) and HIV, to investigate the frequency of TLR4 polymorphism and its role in patients infected with HIV.Materials and methods: We recruited 160 HIV-1 seropositive patients, who were further divided on disease severity based on CD4 count (stages I, II and III), and 270 age- and sex matched healthy HIV-1 seronegative individuals. Subjects were genotyped for TLR4 gene polymorphism by polymerase chain reaction restriction fragment length polymorphism.Results: The TLR4 Asp299Gly heterozygous genotype (OR=2.160; p=0.004) and the mutant allele G (OR=2.051; p=0.002) was higher in HIV-1 infection than healthy controls and also in stage I (OR=2.559; p=0.034) compared to different clinical stages of infection. There was no link between the Thr399Ile polymorphism and HIV infection.Conclusion: The TLR4 (Asp299Gly) SNP is a risk factor in HIV-1 disease susceptibility.

TLR9 polymorphism correlates with immune activation, CD4 decline and plasma IP10 levels in HIV patients

BackgroundThe mechanism behind HIV mediated immune activation remains debated, although the role of virus replication in this process is increasingly evident. Toll like Receptor 9 (TLR9) has been implicated in HIV mediated immune activation via sensing of viral CpG DNA. Polymorphisms in the TLR9 gene and promoter region including TLR9 1635A/G and 1486C/T have been found to be associated with multiple infectious diseases and cancers.MethodsIn the current study, we looked at the correlation of TLR9 polymorphisms 1635A/G and 1486C/T with key hallmarks of HIV disease in a cohort of 50 HIV infected patients. We analyzed CD4 counts, T cell immune activation characterized by upregulation of CD38 and HLA-DR and upregulation of plasma biomarkers of inflammation like LPS, sCD14, IL-6 and IP10 in the HIV patient cohort and compared it to healthy controls.ResultsWe found that TLR9 1635AA genotype was associated with lower CD4 counts and significantly higher immune activation in both CD4+ and CD8+ T cells. Analysis of HIV associated plasma biomarkers including LPS, sCD14, IL-6 and IP10 revealed a strong correlation between IP10 and immune activation. Interestingly, IP10 levels were also found to be higher in HIV patients with the 1635AA genotype. Furthermore, the TLR9 1486C/T polymorphism that is in linkage disequilibrium with 1635A/G was weakly associated with lower CD4 counts, higher CD8 immune activation and higher IP10 levels.ConclusionsAs TLR9 stimulation is known to induce IP10 production by dendritic cells, our findings provide new insights into HIV mediated immune activation and CD4 loss. TLR9 stimulation by viral CpG DNA may be important to HIV immunopathogenesis and the TLR9 polymorphisms 1635A/G and 1486C/T may be associated with disease progression.