Functional consequences of toll-like receptor 4 polymorphisms. Mol Med

Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Molecular Medicine (Impact Factor: 4.51). 05/2008; 14(5-6):346-52. DOI: 10.2119/2007-00135.Ferwerda
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Toll-like receptor 4 (TLR4) is an important pathogen recognition receptor that recognizes mainly lipopolysaccharide (LPS) of Gram-negative bacteria, but also structures from fungal and mycobacterial pathogens, as well as endogenous ligands. Two nonsynonymous polymorphisms of TLR4, Asp299Gly and Thr399Ile, have been suggested to alter the function of the receptor. Some, but not all, studies have proposed that these polymorphisms lead to reduced cytokine response and increased susceptibility to Gram-negative infections. In this review, we compare studies that assessed the effect of the Asp299Gly and Thr399Ile polymorphisms on susceptibility to Gram-negative infections and examine the phenotypic consequences of these polymorphisms. In addition, we review the geographical distribution of TLR4 polymorphisms and present a model for evolutionary pressures on the TLR4 genetic make-up.

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Available from: Karlijn Verheijen, Oct 04, 2015
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    • "TLRs identify these PAMPs and activate innate cells for humoral complement activation during infection that opsonise and kill pathogens (Mogensen, 2009). TLR4 mainly recognize lipopolysaccharides (LPS) of gram-negative bacteria (Ferwerda et al., 2008) and are expressed on many innate cells and mastocytes which activate immune and inflammatory responses against invaders (Baines et al., 2011; Qing et al., 2013). TLR family is characterized by leucinerich repeats (LRR) and a cytoplasmic toll/interleukin-1 receptor domain, which initiates common signalling pathways (Carvalho et al., 2008; Coscia et al., 2011; Roach et al., 2013) such as MyD88-dependent pathway (Krishnan et al., 2007) which activates transcription factors like NF-jB (nuclear factor kappalight-chain-enhancer of activated B cells) and interferon regulatory factors (IRF3) (Davoodi et al., 2012) that regulate the expression of interferons, inflammatory cytokines and chemokines or increase the production of IL12 (Romagnani, 2004) which differentiate naive T cells into Th1 cells and disturb the Th1/Th2 balance in asthma and allergic rhinitis (Neill & Bowie, 2007). "
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    ABSTRACT: Toll-like receptor 4 (TLR4) is the most important TLR among the pattern recognition receptors which recognizes lipopolysaccharide of gram-negative bacteria. They identify a highly conserved structure of microbes called pathogen-associated molecular patterns and activate immune and inflammatory responses that have been shown to be involved in the pathogenesis of asthma. The role of TLR4 gene polymorphisms in asthma was detected in a total of 964 individuals, including 483 healthy controls and 481 asthma patients from a North Indian population. The genotyping was carried out using polymerase chain reaction–restriction fragment length polymorphism method. Statistical analysis revealed that the heterozygous genotype as well as the mutant (T) allele of the TLR4 C>1196T (Thr399Ile) polymorphism shows resistance towards asthma with OR = 0.70, 95% CI (0.49–0.99), P corrected value = 0.046 and OR = 0.72, 95% CI (0.52–0.98), P corrected value = 0.039, respectively. However, no association was found between the TLR4 A>896G (Asp299Gly) polymorphism and asthma patients (P > 0.05). This is the first study conducted in India conferring TLR4 (Thr399Ile) polymorphism resistance towards asthma, while lack of association was found between TLR4 (Asp299Gly) polymorphism and asthma in the studied North Indian population.
    International Journal of Immunogenetics 10/2014; 41(6). DOI:10.1111/iji.12115 · 1.25 Impact Factor
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    • "This observation suggests that TLR4-MyD88 signaling pathway plays a role in the development of liver tumor [42]. Although the main ligand for TLR4 is the bacteria endotoxin lipopolysaccharides (LPS) [12], it was also found that several HCV proteins, such as nonstructural protein 5A (NS5A), core, and NS3, stimulate TLR4 pathway [21]. Due to the importance of TLR4 in innate immunity, several studies have examined the role of TLR4 polymorphism in human diseases. "
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    ABSTRACT: Hepatitis C virus (HCV) is a single stranded RNA virus. It affects millions of people worldwide and is considered as a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. A recent study reported that TLR4 gene polymorphisms are good prognostic predictors and are associated with protection from liver fibrosis among Caucasians. This study aims to investigate the implication of genetic polymorphisms of TLR4 gene on the HCV infection in Saudi Arabian patients. Two SNPs in the TLR4 gene, rs4986790 (A/G) and rs4986791 (C/T), were genotyped in 450 HCV patients and 600 uninfected controls. The association analysis confirmed that both SNPs showed a significant difference in their distribution between HCV-infected patients and uninfected control subjects (P < 0.0001; OR = 0.404, 95% CI = 0.281-0.581) and (P < 0.0001; OR = 0.298, 95% CI = 0.201-0.443), respectively. More importantly, haplotype analysis revealed that four haplotypes, AC, GT, GC, and AT (rs4986790, rs4986791), were significantly associated with HCV infection when compared with control subjects. One haplotype AC was more prominently found when chronic HCV-infected patients were compared with cirrhosis/HCC patients (frequency = 94.7% and P = 0.04). Both TLR4 SNPs under investigation were found to be significantly implicated with HCV-infection among Saudi Arabian population.
    BioMed Research International 08/2014; 2014:357062. DOI:10.1155/2014/357062 · 3.17 Impact Factor
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    • "Although some studies have shown a relevance of the Asp299Gly/Thr399Ile SNPs in gram-negative infections, others did not confirm this association [20-22]. Furthermore, recent studies using primary cells isolated from individuals bearing these mutations have indicated that the Asp299Gly/Thr399Ile haplotype has little or no effect on LPS responsiveness [23]. "
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    ABSTRACT: Background Toll-like receptor 4 (TLR4), a lipopolysaccharide (LPS) receptor complex signal-transducing molecule, plays a crucial role in sensing LPS from gram-negative bacteria. TLR4 signaling pathway activation by LPS plays a major role in sepsis pathogenesis. A single nucleotide polymorphism, rs11536889, in the 3’-untranslated region of the TLR4 gene is thought to affect TLR4 translation. This study aimed to investigate whether organ failure in sepsis patients is related to the TLR4 rs11536889 genotype. Methods Adult Caucasian patients with sepsis from the intensive care unit of a university medical center were followed up for 90 days, and organ failure was recorded as the primary outcome variable. Blood samples were collected at enrollment for TLR4 rs11536889 genotyping. Sepsis-related organ failure assessment (SOFA) scores were quantified at sepsis onset and throughout the observational period to monitor organ failure. Results A total of 210 critically ill patients with sepsis were enrolled into this study. Wild-type GG was compared to GC/CC. During their stay in the intensive care unit, GG patients presented significantly higher SOFA scores than did C allele carriers (7.9 ± 4.5 and 6.8 ± 4.2, respectively; p = 0.0005). Analysis of organ-specific SOFA sub-scores revealed significant differences in three organ systems: renal, coagulation and hepatic (p = 0.0005, p = 0.0245 and p < 0.0001, respectively). Additionally, the rs11536889 polymorphism was associated with a higher incidence of gram-negative infections. Conclusions These results offer the first evidence that TLR4 rs11536889 is a useful marker of organ failure in patients with sepsis.
    Journal of Translational Medicine 06/2014; 12(1):177. DOI:10.1186/1479-5876-12-177 · 3.93 Impact Factor
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